Dna alkylating agents

ABSTRACT

wherein the variables are defined herein, processes of making them, and methods of treating cancer comprising administering such compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 15/557,053, filed on Sep. 8, 2017, which is a national stageapplication under 35 U.S.C. § 371 of International Application No.PCT/US2016/021581, filed Mar. 9, 2016, which in turn claims priorityunder 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No.62/131,163, filed Mar. 10, 2015, and U.S. Provisional Patent ApplicationNo. 62/255,916, filed Nov. 16, 2015, the content of each of which ishereby incorporated by reference in its entirety.

FIELD OF INVENTION

The present invention provides compounds suitable as therapeutic agentsand intermediates thereto, pharmaceutical compositions of such compoundsand methods of treating cancer in cancer patients, and so relates to thefields of biology, chemistry, and medicine.

BACKGROUND OF THE INVENTION

Cancer is one of the major causes of human morbidity and mortality.Cancer treatment is challenging because it is difficult to kill cancercells without damaging or killing normal cells. Damaging or killingnormal cells during cancer treatment is a cause of adverse side effectsin patients and can limit the amount of anti-cancer drug administered toa cancer patient.

Aldo-keto reductase family 1 member C3 is an enzyme that in humans isencoded by the AKR1C3 gene. This gene encodes a member of the aldo/ketoreductase superfamily, which consists of more than 40 known enzymes andproteins. These enzymes catalyze the conversion of aldehydes and ketonesto their corresponding alcohols by utilizing NADH and/or NADPH ascofactors.

Many cancer cells overexpress AKR1C3 reductase relative to normal cells(See, Cancer Res 2010; 70:1573-1584, Cancer Res 2010; 66: 2815-2825).

PR 104:

has been shown to be a weak substrate for AKR1C3 and was tested in theclinical trials. This compound is not a selective AKR1C3 activatedprodrug as it can also be activated under hypoxic conditions. PR 104 wasineffective in clinical trials.

There remains a need for compounds suitable for treating cancerpatients, including for selective AKR1C3 reductase activated prodrugsfor treating cancer patients. The present invention meets this need.

SUMMARY OF THE INVENTION

In one aspect, provided herein are compounds of formula I:

and pharmaceutically acceptable salts, and solvates of each thereof,whereinX¹⁰ is O, S, SO, or SO₂;A is C₆-C₁₀ aryl, 5-15 membered heteroaryl, or —N═CR¹R²;each R¹ and R² independently is hydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl,C₆-C₁₀ aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether,—CONR¹³R¹⁴ or —NR¹³COR¹⁴;each X, Y, and Z independently is hydrogen, CN, halo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4-15 memberedheterocycle, 5-15 membered heteroaryl, ether, —CONR¹³R¹⁴, or —NR¹³COR¹⁴;R is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4-15 membered heterocycle, 5-15 memberedheteroaryl, ether, —CONR¹³R¹⁴, or —NR¹³COR¹⁴;each R¹³ and R¹⁴ independently is hydrogen, C₁-C₆ alkyl, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4-15 membered heterocycle, 5-15 memberedheteroaryl, or ether;T comprises a phosphoramidate alkylating agent; andwherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle,heteroaryl, ether groups are optionally substituted.

In another embodiment, provided herein is a compound of formula I-A

In another embodiment, X¹⁰ is S.

In one embodiment, T is OP(Z¹)(NR³⁰CH₂CH₂X¹)₂, OP(Z¹)(NR³⁰₂)(N(CH₂CH₂X¹)₂) OP(Z¹)(N(CH₂CH₂))₂, OP(Z¹)(N(CH₂CH₂X¹)₂)₂, wherein eachR³⁰ independently is hydrogen or C₁-C₆ alkyl or 2 R³⁰s together with thenitrogen atom they are bound to form 5-7 membered heterocyclyl group, Z¹is O or S, and X¹ is Cl, Br, or OMs or another leaving group. In oneembodiment, T is OP(Z¹)(NHCH₂CH₂Cl)₂, OP(Z¹)(NHCH₂CH₂Br)2,OP(Z¹)(NH₂)(N(CH₂CH₂X¹)₂) OP(Z¹)(N(CH₂)₂)₂, OP(Z¹)(N(CH₂CH₂Cl)₂)₂,wherein Z¹ is O or S, and X¹ is Cl, Br, or OMs. In one embodiment, Z¹ isO. In another embodiment, Z¹ is S. In another embodiment, T isOP(O)(N(CH₂CH₂))₂.

The compounds provided herein include individual diastereomers and othergeometric isomers, and enantiomers, and mixtures of enantiomers,diastereomers, and geometric isomers other than diastereomers.

In another aspect, provided herein is a pharmaceutical compositioncomprising a compound provided herein and at least one pharmaceuticallyacceptable excipient. In another aspect, provided herein is a unit doseof the pharmaceutical composition provided herein.

In another aspect, provided herein is a method for treating cancer in apatient, comprising administering to the patient a therapeuticallyeffective amount of a compound or a pharmaceutically acceptablecomposition as provided herein. In one embodiment, the cancer is onewherein AKR1C3 reductase levels are high or are higher than usual insuch a cancer. In one embodiment, the cancer is liver cancer. In oneembodiment, the cancer is non-small cell lung cancer or melanoma. In afurther aspect, the method comprises determining the AKR1C3 reductaselevel of the cancer by methods using an AKR1C3 antibody, andadministering a therapeutically effective amount of a compound or apharmaceutically acceptable composition provided herein to said patientif said level is equal to or greater than a predetermined value. In oneaspect, the method comprises prior to administration, determining anintratumoral AKR1C3 reductase level in a sample isolated from thepatient and selecting the patient for the therapy if the level is equalto or greater than a predetermined level. In some embodiments, atherapeutically effective amount of a cancer treatment other than atreatment comprising administration of a compound or a pharmaceuticallyacceptable composition provided herein is administered if the level doesnot exceed or is less than said predetermined value. In someembodiments, provided herein is a kit comprising a means for isolating asample from a patient and determining an intratumoral AKR1C3 reductaselevel of the cancer in the sample using an AKR1C3 antibody; and a meansfor determining whether a compound or composition provided herein shouldbe administered. Methods of determining the therapeutically effectiveamount, appropriate mode of administration of the compounds andcompositions provided herein will be apparent to the skilled artisanupon reading this disclosure and based on other methods known to them.AKR1C3 levels are measured following routine methods well known to theskilled artisan.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates AKR1C3 expression in liver cancer cell lines.

FIG. 2 illustrates AKR1C3 expression in prostate cancer cell lines.

FIG. 3 illustrates Antitumor efficacy of TH-2768 alone and incombination with irinotecan (CPT-11) in comparison with gemcitabine inthe ectopic H460, NSCLC xenograft model described in Example 4-A.

FIG. 4 illustrates body weight change induced by TH-2768 treatment aloneand in combination with irinotecan (CPT-11) in comparison withgemcitabine in the ectopic H460, NSCLC xenograft model Example 4-A.

FIG. 5 illustrates antitumor efficacy of TH-2768, TH-2850, TH-2852,TH-2870, or TH-2889 in comparison with Thio-TEPA in the ectopic A549,NSCLC xenograft model described in Example 4-B.

FIG. 6 illustrates body weight change induced by TH-2768, TH-2850,TH-2852, TH-2870, or TH-2889 in comparison with Thio-TEPA in the ectopicA549, NSCLC xenograft model described in Example 4-B.

FIG. 7 illustrates antitumor efficacy of TH-2768, TH-2850, TH-2870,TH-2873, TH-2888, TH-2889 or TH-2890 in comparison with Thio-TEPA ornab-Paclitaxel in the ectopic A375, melanoma xenograft model describedin Example 4-C.

FIG. 8 illustrates body weight change induced by TH-2768, TH-2850,TH-2870, TH-2873, TH-2888, TH-2889 or TH-2890 in comparison withThio-TEPA or nab-Paclitaxel in the ectopic A375, melanoma xenograftmodel described in Example 4-C.

FIG. 9 illustrates antitumor efficacy of TH-2870, TH-2883, TH-2911,TH-2952, TH-2953, TH-2955, or TH-2958 in the ectopic A549, NSCLCxenograft model described in Example 4-D.

FIG. 10 illustrates body weight change induced by TH-2870, TH-2883,TH-2911, TH-2952, TH-2953, TH-2955, or TH-2958 in the ectopic A549,NSCLC xenograft model described in Example 4-D.

FIG. 11 illustrates antitumor efficacy of TH-2870 alone or incombination with sunitinib in the ectopic 786-O, RCC xenograft modeldescribed in Example 4-E.

FIG. 12 illustrates body weight change induced by TH-2870 alone or incombination with sunitinib in the ectopic 786-O, RCC xenograft modeldescribed in Example 4-E.

FIG. 13 illustrates antitumor efficacy of TH-2953 or TH-3040 in theectopic H460 NSCLC xenograft model described in Example 4-F.

FIG. 14 illustrates body weight change induced by TH-2953 or TH-3040 inthe ectopic H460 NSCLC xenograft model described in Example 4-F.

FIG. 15 illustrates antitumor efficacy of TH-3040 or TH-3045 in theectopic H460 NSCLC xenograft model described in Example 4-G.

FIG. 16 illustrates body weight change induced by TH-3040 or TH-3045 inthe ectopic H460 NSCLC xenograft model described in Example 4-G.

FIG. 17 illustrates antitumor efficacy of TH-3040 in comparison withnab-paclitaxel in the ectopic H460 NSCLC xenograft model described inExample 4-H.

FIG. 18 illustrates body weight change induced by TH-3040 in comparisonwith nab-paclitaxel in the ectopic H460 NSCLC xenograft model describedin Example 4-H.

FIG. 19 illustrates antitumor efficacy of TH-2870 in comparison withdocetaxel in the ectopic H460 NSCLC xenograft model described in Example4-I.

FIG. 20 illustrates body weight change induced by TH-2870 in comparisonwith docetaxel in the ectopic H460 NSCLC xenograft model described inExample 4-I.

DETAILED DESCRIPTION Definitions

The following definitions are provided to assist the reader. Unlessotherwise defined, all terms of art, notations, and other scientific ormedical terms or terminology used herein are intended to have themeanings commonly understood by those of skill in the chemical andmedical arts. In some cases, terms with commonly understood meanings aredefined herein for clarity and/or for ready reference, and the inclusionof such definitions herein should not be construed as representing asubstantial difference over the definition of the term as generallyunderstood in the art.

All numerical designations, e.g., pH, temperature, time, concentration,and weight, including ranges of each thereof, are approximations thattypically may be varied (+) or (−) by increments of 0.1, 1.0, or 10.0,as appropriate. All numerical designations may be understood as precededby the term “about”. Reagents described herein are exemplary andequivalents of such may be known in the art.

“A,” “an,” and, “the” include plural referents unless the contextclearly dictates otherwise. Thus, for example, reference to a compoundrefers to one or more compounds or at least one compound. As such, theterms “a” (or “an”), “one or more”, and “at least one” are usedinterchangeably herein.

As used herein, the term “comprising” is intended to mean that thecompositions and methods include the recited elements, but not excludingothers. “Consisting essentially of” when used to define compositions andmethods, shall mean excluding other elements of any essentialsignificance to the composition or method. “Consisting of” shall meanexcluding more than trace elements of other ingredients for claimedcompositions and substantial method steps. Embodiments defined by eachof these transition terms are within the scope of this invention.Accordingly, it is intended that the methods and compositions caninclude additional steps and components (comprising) or alternativelyincluding steps and compositions of no significance (consistingessentially of) or alternatively, intending only the stated method stepsor compositions (consisting of).

“C_(x)-C_(y)” or “C_(x-y)” before a group refers to a range of thenumber of carbon atoms that are present in that group. For example,C₁-C₆ alkyl refers to an alkyl group having at least 1 and up to 6carbon atoms.

“Alkoxy” refers to —O-Alkyl.

“Amino” refers to NR^(p)R^(q) wherein R^(p) and R^(q) independently arehydrogen or C₁-C₆ alkyl, or R^(p) and R^(q) together with the nitrogenatom they are bonded to form a 4-15 membered heterocycle.

“Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groupshaving from 1 to 10 carbon atoms and, in some embodiments, from 1 to 6carbon atoms. “C_(x-y) alkyl” refers to alkyl groups having from x to ycarbon atoms. This term includes, by way of example, linear and branchedhydrocarbyl groups such as methyl (CH₃—), ethyl (CH₃CH₂—), n-propyl(CH₃CH₂CH₂—), isopropyl ((CH₃)₂CH—), n-butyl (CH₃CH₂CH₂CH₂—), isobutyl((CH₃)₂CHCH₂—), sec-butyl ((CH₃)(CH₃CH₂)CH—), t-butyl ((CH₃)₃C—),n-pentyl (CH₃CH₂CH₂CH₂CH₂—), and neopentyl ((CH₃)₃CCH₂—).

“Alkylene” refers to divalent saturated aliphatic hydrocarbyl groupshaving from 1 to 10 carbon atoms and, in some embodiments, from 1 to 6carbon atoms. “C_(u-v)alkylene” refers to alkylene groups having from uto v carbon atoms. The alkylidene and alkylene groups include branchedand straight chain hydrocarbyl groups. For example, “C₁₋₆ alkylene”includes methylene, ethylene, propylene, 2-methylpropylene, pentylene,and the like. “Heteroalkylene” refers to an alkylene wherein a chaincarbon atom is replaced with a heteroatom such as O, S, N, or P, or aheteroatom containing substituent.

“Alkenyl” refers to a linear or branched hydrocarbyl group having from 2to 10 carbon atoms and in some embodiments from 2 to 6 carbon atoms or 2to 4 carbon atoms and having at least 1 site of vinyl unsaturation(>C═C<). For example, C_(x-y) alkenyl refers to alkenyl groups havingfrom x to y carbon atoms and is meant to include, for example, ethenyl,propenyl, 1,3-butadienyl, and the like. “Alkenylene” refers to adivalent alkenyl radical having the appropriate hydrogen content.“Heteroalkenylene” refers to an alkenylene wherein a chain carbon atomis replaced with a heteroatom such as O, S, N, or P, or a heteroatomcontaining substituent.

“Phosphoramidate alkylating agent” refers to an alkylating agentcomprising one or more Z⁵—X⁵—Y⁵ moieties bonded to an —O—P(Z¹) moiety,where Z⁵ is a heteroatom such as nitrogen, sulfur or oxygen, X⁵ isoptionally substituted ethylene, Y⁵ is halo or another leaving group, orZ⁵—X⁵—Y⁵ together form an aziridinyl (NCH₂CH₂) moiety, and Z¹ is definedas above. Such an alkylating agent can react with a DNA or anothernucleic acid, or a protein. In some instances an alkylating agent cancross link a DNA.

“Alkynyl” refers to a linear monovalent hydrocarbon radical or abranched monovalent hydrocarbon radical 2 to 10 carbon atoms and in someembodiments from 2 to 6 carbon atoms or 2 to 4 carbon atoms andcontaining at least one triple bond. The term “alkynyl” is also meant toinclude those hydrocarbyl groups having one triple bond and one doublebond. For example, C₂₋₆ alkynyl includes ethynyl, propynyl, and thelike. “Alkynylene” refers to a divalent alkynyl radical having theappropriate hydrogen content. “Heteroalkynylene” refers to an alkynylenewherein a chain carbon atom is replaced with a heteroatom such as O, S,N, or P, or a heteroatom containing substituent.

“Aryl” refers to an aromatic group of from 6 to 14 carbon atoms and noring heteroatoms and having a single ring (e.g., phenyl) or multiplecondensed (fused) rings (e.g., naphthyl or anthryl). For multiple ringsystems, including fused, bridged, and spiro ring systems havingaromatic and non-aromatic rings that have no ring heteroatoms, the term“Aryl” or “Ar” applies when the point of attachment is at an aromaticcarbon atom (e.g., 5, 6, 7, 8 tetrahydronaphthalene-2-yl is an arylgroup as its point of attachment is at the 2-position of the aromaticphenyl ring). “Arylene” refers to a divalent aryl radical having theappropriate hydrogen content.

“Cycloalkyl” refers to a saturated or partially saturated cyclic groupof from 3 to 14 carbon atoms and no ring heteroatoms and having a singlering or multiple rings including fused, bridged, and spiro ring systems.For multiple ring systems having aromatic and non-aromatic rings thathave no ring heteroatoms, the term “cycloalkyl” applies when the pointof attachment is at a non-aromatic carbon atom (e.g.5,6,7,8-tetrahydronaphthalene-5-yl). The term “cycloalkyl” includescycloalkenyl groups. Examples of cycloalkyl groups include, forinstance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl,and cyclohexenyl. “Cycloalkylene” refers to a divalent cycloalyl radicalhaving the appropriate hydrogen content.

“Ether” refers to a C₁-C₆ alkyl group substituted with 1-3 C₁-C₆ alkoxygroups, wherein alkoxy refers to —O-alkyl.

“Halo” refers to one or more of fluoro, chloro, bromo, and iodo.

“Heteroaryl” refers to an aromatic group of from 1 to 14 carbon atomsand 1 to 6 heteroatoms selected from the group consisting of oxygen,nitrogen, and sulfur and includes single ring (e.g. imidazolyl-2-yl andimidazol5-yl) and multiple ring systems (e.g. imidazopyridyl,benzotriazolyl, benzimidazol-2-yl and benzimidazol-6-yl). For multiplering systems, including fused, bridged, and spiro ring systems havingaromatic and non-aromatic rings, the term “heteroaryl” applies if thereis at least one ring heteroatom, and the point of attachment is at anatom of an aromatic ring (e.g. 1,2,3,4-tetrahydroquinolin-6-yl and5,6,7,8-tetrahydroquinolin-3-yl). In some embodiments, the nitrogenand/or the sulfur ring atom(s) of the heteroaryl group are optionallyoxidized to provide for the N-oxide (N→O), sulfinyl, or sulfonylmoieties. The term heteroaryl includes, but is not limited to,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl,benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzothienyl,benzimidazolinyl, carbazolyl, NH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, dithiazinyl, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazopyridyl, imidazolyl, indazolyl, indolenyl,indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isoquinolyl,isothiazolyl, isoxazolyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, oxazolidinyl, oxazolyl, pyrimidinyl, phenanthridinyl,phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl,phenoxazinyl, phthalazinyl, piperazinyl, pteridinyl, purinyl, pyranyl,pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,pyridooxazolyl, pyridoimidazolyl, pyridothiazole, pyridinyl, pyridyl,pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl,quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,tetrazolyl, thiadiazinyl, thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl and xanthenyl. “Heteroarylene” refers to a divalent heteroarylradical having the appropriate hydrogen content.

“Heterocyclic” or “heterocycle” or “heterocycloalkyl” or “heterocyclyl”refers to a saturated or partially saturated cyclic group having from 1to 14 carbon atoms and from 1 to 6 heteroatoms selected from the groupconsisting of nitrogen, sulfur, or oxygen and includes single ring andmultiple ring systems including fused, bridged, and spiro ring systems.For multiple ring systems having aromatic and/or non-aromatic rings, theterms “heterocyclic”, “heterocycle”, “heterocycloalkyl”, or“heterocyclyl” apply when there is at least one ring heteroatom, and thepoint of attachment is at an atom of a non-aromatic ring (e.g.1,2,3,4-tetrahydroquinoline-3-yl, 5,6,7,8-tetrahydroquinoline-6-yl, anddecahydroquinolin-6-yl). In some embodiment, the heterocyclic groupsherein are 3-15 membered, 4-14 membered, 5-13 membered, 7-12, or 5-7membered heterocycles. In some other embodiment, the heterocyclescontain 4 heteroatoms. In some other embodiment, the heterocyclescontain 3 heteroatoms. In another embodiment, the heterocycles containup to 2 heteroatoms. In some embodiments, the nitrogen and/or sulfuratom(s) of the heterocyclic group are optionally oxidized to provide forthe N-oxide, sulfinyl, sulfonyl moieties. Heterocyclyl includes, but isnot limited to, tetrahydropyranyl, piperidinyl, N-methylpiperidin-3-yl,piperazinyl, N-methylpyrrolidin-3-yl, 3-pyrrolidinyl, 2-pyrrolidon-1-yl,morpholinyl, and pyrrolidinyl. A prefix indicating the number of carbonatoms (e.g., C₃₋₁₀) refers to the total number of carbon atoms in theportion of the heterocyclyl group exclusive of the number ofheteroatoms. A divalent heterocyclic radical will have the appropriatelyadjusted hydrogen content.

“Leaving group” refers to a moiety that can be displaced undernucleophilic displacement conditions well known to the skilled artisan.Leaving groups include, without limitation halo and —OSO₂—R²⁰, where R²⁰is optionally substituted alkyl, aryl, cycloalkyl, heterocyclyl, orheteroaryl.

The term “optionally substituted” refers to a substituted orunsubstituted group. The group may be substituted with one or moresubstituents, such as e.g., 1, 2, 3, 4 or 5 substituents. Preferably,the substituents are selected from the group consisting of oxo, halo,—CN, NO₂, —N₂+, —CO₂R¹⁰⁰, —SR¹⁰⁰, —SOR¹⁰⁰, —SO₂R¹⁰⁰, —NR¹⁰⁰SO²R¹⁰⁰,—NR¹⁰¹R¹⁰², —CONR¹⁰¹R¹⁰², —SO₂NR¹⁰¹R¹⁰², C₁-C₆ alkyl, C₁-C₆ alkoxy,—CR¹⁰⁰═C(R¹⁰⁰)₂, CCR¹⁰⁰, C₃-C₁₀ cycloalkyl, C₃-C₁₀ heterocyclyl, C₆-C₁₂aryl and C₂-C₁₂ heteroaryl, or a divalent substituent such as—O—(CH₂)—O—, —O—(CH₂)₂—O—, and, 1-4 methyl substituted version thereof,wherein each R¹⁰⁰, R¹⁰¹, and R¹⁰² independently is hydrogen or C₁-C₈alkyl; C₃-C₁₂ cycloalkyl; C₃-C₁₀ heterocyclyl; C₆-C₁₂ aryl; or C₂-C₁₂heteroaryl; or R¹⁰¹ and R¹⁰² together with the nitrogen atom they areattached to form a 5-7 membered heterocycle; wherein each alkyl,cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substitutedwith 1-3 halo, 1-3 C₁-C₆ alkyl, 1-3 C₁-C₆ haloalkyl or 1-3 C₁-C₆ alkoxygroups. Preferably, the substituents are selected from the groupconsisting of chloro, fluoro, —OCH₃, methyl, ethyl, iso-propyl,cyclopropyl, —CO₂H and salts and C₁-C₆ alkyl esters thereof, CONMe₂,CONHMe, CONH₂, —SO₂Me, —SO₂NH₂, —SO₂NMe₂, —SO₂NHMe, —NHSO₂Me, —NHSO₂CF₃,—NHSO₂CH₂Cl, —NH₂, —OCF₃, —CF₃ and —OCHF₂.

“Administering” or “administration of” a drug to a patient (andgrammatical equivalents of this phrase) refers to direct administration,which may be administration to a patient by a medical professional ormay be self-administration, and/or indirect administration, which may bethe act of prescribing a drug. For example, a physician who instructs apatient to self-administer a drug and/or provides a patient with aprescription for a drug is administering the drug to the patient.

“Cancer” refers to leukemias, lymphomas, carcinomas, and other malignanttumors, including solid tumors, of potentially unlimited growth that canexpand locally by invasion and systemically by metastasis. Examples ofcancers include, but are not limited to, cancer of the adrenal gland,bone, brain, breast, bronchi, colon and/or rectum, gallbladder, head andneck, kidneys, larynx, liver, lung, neural tissue, pancreas, prostate,parathyroid, skin, stomach, and thyroid. Certain other examples ofcancers include, acute and chronic lymphocytic and granulocytic tumors,adenocarcinoma, adenoma, basal cell carcinoma, cervical dysplasia and insitu carcinoma, Ewing's sarcoma, epidermoid carcinomas, giant celltumor, glioblastoma multiforma, hairy-cell tumor, intestinalganglioneuroma, hyperplastic corneal nerve tumor, islet cell carcinoma,Kaposi's sarcoma, leiomyoma, leukemias, lymphomas, malignant carcinoid,malignant melanomas, malignant hypercalcemia, marfanoid habitus tumor,medullary carcinoma, metastatic skin carcinoma, mucosal neuroma,myeloma, mycosis fungoides, neuroblastoma, osteo sarcoma, osteogenic andother sarcoma, ovarian tumor, pheochromocytoma, polycythermia vera,primary brain tumor, small-cell lung tumor, squamous cell carcinoma ofboth ulcerating and papillary type, hyperplasia, seminoma, soft tissuesarcoma, retinoblastoma, rhabdomyosarcoma, renal cell tumor, topicalskin lesion, veticulum cell sarcoma, and Wilm's tumor.

“Patient” and “subject” are used interchangeably to refer to a mammal inneed of treatment for cancer. Generally, the patient is a humanGenerally, the patient is a human diagnosed with cancer. In certainembodiments a “patient” or “subject” may refer to a non-human mammalused in screening, characterizing, and evaluating drugs and therapies,such as, a non-human primate, a dog, cat, rabbit, pig, mouse or a rat.

“Prodrug” refers to a compound that, after administration, ismetabolized or otherwise converted to a biologically active or moreactive compound (or drug) with respect to at least one property. Aprodrug, relative to the drug, is modified chemically in a manner thatrenders it, relative to the drug, less active or inactive, but thechemical modification is such that the corresponding drug is generatedby metabolic or other biological processes after the prodrug isadministered. A prodrug may have, relative to the active drug, alteredmetabolic stability or transport characteristics, fewer side effects orlower toxicity, or improved flavor (for example, see the referenceNogrady, 1985, Medicinal Chemistry A Biochemical Approach, OxfordUniversity Press, New York, pages 388-392, incorporated herein byreference). A prodrug may be synthesized using reactants other than thecorresponding drug.

“Solid tumor” refers to solid tumors including, but not limited to,metastatic tumors in bone, brain, liver, lungs, lymph node, pancreas,prostate, skin and soft tissue (sarcoma).

“Therapeutically effective amount” of a drug refers to an amount of adrug that, when administered to a patient with cancer, will have theintended therapeutic effect, e.g., alleviation, amelioration, palliationor elimination of one or more manifestations of cancer in the patient. Atherapeutic effect does not necessarily occur by administration of onedose, and may occur only after administration of a series of doses.Thus, a therapeutically effective amount may be administered in one ormore administrations.

“Treating,” “treatment of,” or “therapy of” a condition or patientrefers to taking steps to obtain beneficial or desired results,including clinical results. For purposes of this invention, beneficialor desired clinical results include, but are not limited to, alleviationor amelioration of one or more symptoms of cancer; diminishment ofextent of disease; delay or slowing of disease progression;amelioration, palliation, or stabilization of the disease state; orother beneficial results. Treatment of cancer may, in some cases, resultin partial response or stable disease.

“Tumor cells” refers to tumor cells of any appropriate species, e.g.,mammalian such as murine, canine, feline, equine or human.

Descriptive Embodiments

Provided herein are compound of formulas I as disclosed herein above.

In one aspect, provided herein are compounds of formula I-A:

and pharmaceutically acceptable salts and solvates thereof, whereinA is C₆-C₁₀ aryl, 5-15 membered heteroaryl, or —N═CR¹R²;each R¹ and R² independently is hydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl,C₆-C₁₀ aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether,—CONR¹³R¹⁴ or —NR¹³COR¹⁴;each X, Y, and Z independently is hydrogen, CN, halo, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4-15 memberedheterocycle, 5-15 membered heteroaryl, ether, —CONR¹³R¹⁴, or —NR¹³COR¹⁴;R is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4-15 membered heterocycle, 5-15 memberedheteroaryl, ether, —CONR¹³R¹⁴, or —NR¹³COR¹⁴;each R¹³ and R¹⁴ independently is hydrogen, C₁-C₆ alkyl, C₃-C₈cycloalkyl, C₆-C₁₀ aryl, 4-15 membered heterocycle, 5-15 memberedheteroaryl, or ether;wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle,heteroaryl, ether groups are optionally substituted; andT is a phosphoramidate alkylating agent.

In one embodiment, Z is hydrogen. In another embodiment, X is hydrogen.In another embodiment, Y is hydrogen. In another embodiment, Y is halo.

In another embodiment, A is optionally substituted C₆-C₁₀ aryl. Inanother embodiment, A is optionally substituted phenyl. In anotherembodiment, the phenyl is optionally substituted with 1-3, 1-2, or asubstituent selected from halo, —CN, NO₂, —CO₂R¹⁰⁰, —OR¹⁰⁰, SR¹⁰⁰,—SOR¹⁰⁰, SO₂R¹⁰⁰, —NR¹⁰⁰SO₂R¹⁰⁰, —NR¹⁰¹R¹⁰², —CONR¹⁰¹R¹⁰², —SO₂R¹⁰¹R¹⁰²,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₁₀ cycloalkyl, C₃-C₁₀ heterocyclyl,C₆-C₁₂ aryl and C₂-C₁₂heteroaryl, or a divalent substituent such as—O—(CH₂)—O—, —O—(CH₂)₂—O—, wherein each R¹⁰⁰, R¹⁰¹, and R¹⁰²independently is hydrogen or C₁-C₈ alkyl; C₃-C₁₂ cycloalkyl; C₃-C₁₀heterocyclyl; C₆-C₁₂ aryl; or C₂-C₁₂heteroaryl; or R¹⁰¹ and R¹⁰²together with the nitrogen atom they are attached to form a 5-7 memberedheterocycle; wherein each alkyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl is optionally substituted with 1-3 halo, 1-3 C₁-C₆ alkyl, 1-3C₁-C₆ haloalkyl or 1-3 C₁-C₆ alkoxy groups.

In another embodiment, A is optionally substituted 5-15 memberedheteroaryl. In another embodiment, A is optionally substituted pyridyl.In another embodiment, A is optionally substituted benzothiazolyl.

In another embodiment, A is —N═CR¹R² where R¹ and R² are defined asherein.

In some embodiments, R is hydrogen. In some embodiments, R is C₁-C₆alkyl. In some embodiments, R is methyl.

In certain embodiments, suitable substituents for A is disclosed as partof the specific compounds tabulated herein below.

In one embodiment, T is OP(Z)(NHCH₂CH₂C₁)₂, OP(Z)(NHCH₂CH₂Br)₂,OP(Z)(NH₂)(N(CH₂CH₂X)₂) OP(Z)(N(CH₂)₂)₂, OP(Z)(N(CH₂CH₂C₁)₂)₂; Z═O or S;and X═Cl, Br, and OMs (—OSO₂Me).

In another embodiment, T is OP(O)(NHCH₂CH₂Cl)₂. In another embodiment, Tis OP(O)(NHCH₂CH₂Br)₂. In another embodiment, T isOP(O)(NH₂)(N(CH₂CH₂C₁)₂).

In another embodiment, provided herein is a compound tabulated below ora pharmaceutically acceptable salt or a solvate of each thereof; itsanti-proliferation efficacy on H460 lung cancer cells is also tabulated.

IC 50 in proliferation Compound assay in H460 cells number Structure(uM) 2768

0.04 2846

0.06 2850

0.02 2852

0.02 2853

<0.005 2854

<0.005 2855

0.03 2860

0.01 2861

0.02 2862

0.04 2863

0.02 2864

0.02 2865

0.03 2866

0.02 2870

0.0004 2871

0.03 2872

0.03 2873

0.005 2874

0.5 2875

3.2 2876

0.003 2877

0.02 2878

4.4 2880

0.1 2881

0.03 2882

3.4 2883

0.03 2884

0.01 2885

3.7 2887

0.2 2888

0.003 2889

0.003 2890

0.006 2891

0.03 2892

0.002 2893

0.02 2895

0.004 2896

0.1 2898

0.01 2899

0.004 2900

0.04 2901

0.003 2902

0.09 2903

0.03 2904

0.01 2906 (Comparative example)

4 2908

0.007 2909

0.01 2910

3.5 2911

0.008 2912

0.04 2913

0.07 2914

0.03 2915

0.09 2916

0.12 2917

0.02 2918

0.003 2919

0.004 2920

0.02 2921

0.007 2922

0.003 2923

0.02 2924

0.1 2925

0.04 2926

0.02 2927

0.003 2928

0.03 2929

0.03 2930

0.002 2931

0.001 2932

0.02 2933

0.1 2934

0.003 2935

0.02 2937

0.002 2938

2.5 2939

2.7 2940

0.005 2941

0.004 2942

0.02 2944

>5 2945

0.05 2946

0.03 2947

0.2 2948

0.04 2949

0.4 2950

0.04 2951

0.02 2952

0.003 2953

0.005 2954

0.1 2955

0.006 2956

0.004 2957

0.04 2958

0.002 2960

1.6 2961

2.7 2966

0.2 2967

0.1 2968

0.004 2969

0.002 2970

0.04 2971

0.003 2972

0.01 2973

0.02 2974

0.001 2978

0.002 2980

3 2981

3.7 2982

0.004 2983

0.004 2984

0.005 2985

0.004 2991

0.006 2992

0.004 2993

0.02 3028

0.7 3029

0.6 3030

0.02 3031

0.01 3032

0.003 3033

0.001 3034

0.008 3035

0.001 3036

0.004 3037

0.001 3040

0.004 3041

0.05 3042

0.005 3045

0.004 3050

0.01

In another aspect, provided herein is a process of preparing a compoundof formula I comprising contacting a compound of formula II:

wherein L is a leaving group, with a compound of formula III:

and optionally a base to provide a compound of formula I, wherein theremaining variables are defined in any aspect or embodiment, as above.

In one embodiment, L is halo. In another embodiment, L is F. In anotherembodiment, X¹⁰ is O. In another embodiment, Z is hydrogen. In anotherembodiment, X is hydrogen. In another embodiment, Y is hydrogen. Inanother embodiment, Y is halo. In one embodiment, the base is a string,non-nucleophilic base, as is well known to the skilled artisan. In oneembodiment, the base is a hydride base.

Certain methods for synthesizing compounds provided herein are providedherein. Other methods for synthesizing these and other compoundsprovided herein will be apparent to the skilled artisan based on theadaptation of, and the replacement of reagents and reactants in,synthetic methods well known to them. See, e.g., Hay et al., J. Med.Chem. 2003, 46, 2456-2466 and Hu et al., Bioorganic & MedicinalChemistry Letters 21 (2011) 3986-3991. Starting materials useful forpreparing the compounds provided herein are commercially available orcan be prepared following routine methods. The reactions are commonlycarried out in an inert solvent and heated if necessary. The skilledartisan will readily appreciate that certain reactions may require theuse of a protecting group. Protecting groups are well known to theskilled artisan and described, e.g., in Greene's Protective Groups inOrganic Synthesis. Peter G. M. Wuts and Theodora W. Greene, 4^(th)Edition or a later edition, John Wiley & Sons, Inc., 2007. The reactionproducts may be separated following routine methods such ascrystallization, precipitation, distillation, and/or chromatography. Thepurity of a compound or an intermediate can be ascertained using wellknown methods such as ¹H NMR, HPLC, TLC, and the likes.

EXAMPLES Example 1-A. Preparation of Compound TH 2768

a. Synthesis of Compound 3

Compound 1 (3 g, 16.2 mmol) was refluxed in SOCl₂ (10 mL) with DMF (3drops) for 3 h and then SOCl₂ was removed under vacuum. The residue wasdiluted with toluene (5 mL) and was used in the following step withoutfurther purification.

A mixture of MgCl₂ (930 mg, 9.8 mmol), TEA (4.7 mL, 33.4 mmol) anddimethyl malonate (1.9 mL, 16.6 mmol) was stirred at RT for 1.5 h beforethe above mentioned toluene solution of Compound 2 was added. Theresulting mixture was stirred at RT for another 1.5 h before conc. HCl(4 mL) was added and stirred for 5 minutes. The mixture was extractedwith EtOAc (30 mL×3), dried (Na₂SO₄), filtered and concentrated underreduced pressure.

To the residue was added 6N HCl (30 mL and the mixture was refluxedovernight.

The mixture was extracted with EtOAc (30 mL×3), dried (Na₂SO₄), filteredand concentrated under reduced pressure. The residue was purified viaFCC (silica gel, EtOAc/Hexane) to afford Compound 3 as a light yellowsolid (1.9 g, 63% yield).

1H NMR (CDCl3, 400 MHz) δ: 8.16 (d, J=8.0 Hz, 1H), 7.86 (t, d=9.2 Hz,2H), 2.68 (s, 3H).

b. Synthesis of Compound 4

To a mixture of Compound 3 (1.9 g, 10.4 mmol) in MeOH (20 mL) at −10 Cwas added NaBH₄ (418 mg, 11 mmol) in portions. The mixture was stirredbetween −10 C to 0 C for 20 minutes, diluted with EtOAc (300 mL), washedwith sat. NH₄Cl aqueous solution, brine, dried (Na₂SO₄). Filtered andconcentrated under reduced pressure. The residue was purified via FCC(silica gel, EtOAc/Hexane) to afford Compound 4 as a light yellow oil(1.44 g, 75% yield).

1H NMR (CDCl3, 400 MHz) δ: 8.06 (t, J=8.4 Hz, 1H), 7.35 (d, J=11.6 Hz,1H), 7.30 (d, J=11.6 Hz, 1H), 5.01-4.99 (m, 1H), 1.52 (d, J=6.4 Hz, 3H).

c. Synthesis of Compound 5

To a mixture of Compound 4 (1.44 g, 7.78 mmol), Br-IPM (2.88 g, 9.34mmol), PPh3 (3.06 g, 11.67 mmol) in THF (60 mL) at 0 C was added DIAD(2.34 g, 11.67 mmol). The mixture was stirred at 0 C for 1.5 h,concentrated under reduced pressure and purified via FCC (silica gel,EtOAc/Hexane) to afford Compound 5 as a light yellow oil (1.0 g, 27%yield).

1H NMR (CDCl3, 400 MHz) δ: 8.09 (t, J=8.0 Hz, 1H), 8.31 (dd, J=2.4, 13.6Hz, 2H), 5.52-5.60 (m, 1H), 3.54-3.19 (m, 8H), 1.63 (d, J=6.4 Hz, 3H).

d. Synthesis of Compound 6

A mixture of Compound 5 (1 g, 2.1 mmol) and Ag2O (3 g) in THF (50 mL)was stirred at 65 C for 3 h. Filtered and concentrated under reducedpressure. The residue was purified via FCC (silica gel, Acetone/Hexane)to afford Compound 6 as a yellow solid (0.6 g, 90% yield).

¹H NMR (CDCl3, 400 MHz) δ: 8.08 (t, J=8.0 Hz, 1H), 7.36 (d, J=11.6 Hz,1H), 7.31 (d, J=8.4 Hz, 1H), 5.70-5.67 (m, 1H), 2.25-2.08 (m, 8H), 1.64(d, J=6.4 Hz, 3H).

e. Synthesis of TH 2768

To a mixture of phenol (1.8 g, 19.05 mmol) in DMF (80 mL) at 0 C wasadded NaH (60%, 0.76 g, 19.05) in portions. The mixture was stirred at 0C for 0.5 h before Compound 6 (3 g, 9.53 mmol) was added and thenstirred at 0 C for 2 h. The mixture was diluted with EtOAc (1 L), washedwith brine (100 mL×4), dried over Na₂SO₄, filtered, concentrated underreduced pressure and purified via FCC (silica gel, Acetone/Hexane) toafford TH 2768 as a light brown oil (2.3 g, 62% yield).

Purification of TH 2768

TH 2768 as mentioned above was purified via semi-prep HPLC (c18 column,acetonitrile/water). The combined collections were concentrated underreduced pressure to afford a light yellow oil (0.9 g, 81.8% yield) asthe final product. Acetonitrile was added in the process as an azeotropeagent to remove water.

1H NMR (CDCl3, 400 MHz) δ: 7.96 (d, J=11.6 Hz, 1H), 7.40 (t, J=10.0 Hz,2H), 7.21 (t, J=10.0 Hz, 2H), 7.07-7.03 (m, 3H), 5.61-5.48 (m, 1H),2.22-2.18 (m, 8H), 1.58 (d, J=8.4 Hz, 3H).

Example 1-B. Preparation of TH 2953

Compounds 3-6 were synthesized as described above.

a. Synthesis of TH 2953

To a mixture of 4-phenylphenol (2.16 g, 12.7 mmol) in DMF (60 mL) at 0 Cwas added NaH (60%, 0.508 g, 12.7 mmol) in portions. The mixture wasstirred at 0 C for 0.5 h before Compound 6 (2 g, 6.35 mmol) was addedand then stirred at 0 C for 2.5 h. The mixture was diluted with EtOAc(500 mL), washed with brine (50 mL×3), dried over Na₂SO₄, filtered,concentrated under reduced pressure and purified via FCC (silica gel,Acetone/Hexane) to afford TH 2953 as a yellow oil.

Purification of TH 2953

TH 2953 as mentioned above was purified via semi-prep HPLC (C18 column,acetonitrile/water). The combined collections were concentrated underreduced pressure to afford a light yellow oil (1.83 g, 62% yield) as thefinal product. Acetonitrile was added to the evaporations as anazeotrope agent to remove water.

¹H NMR (CDCl3, 400 MHz) δ: 7.99 (d, J=8.4 Hz, 1H), 7.62-7.57 (m, 4H),7.46 (t, J=7.6 Hz, 2H), 7.37 (t, J=7.2 Hz, 1H), 7.23 (dd, J=8.4, 1.6 Hz,1H), 7.13-7.11 (m, 3H), 5.61-5.58 (m, 1H), 2.22-1.81 (m, 8H), 1.58 (d,J=6.8 Hz, 3H) ppm.

Example 1-C. Preparation of Compound TH 2870

Compounds 2-6 were synthesized as described below.

a. Synthesis of Compound 3

Compound 1 (3 g, 16.2 mmol) was refluxed in SOCl₂ (10 mL) with DMF (3drops) for 3 h and then SOCl₂ was removed under vacuum. The residue wasdiluted with toluene (5 mL) and was used in the following step withoutfurther purification.

A mixture of MgCl₂ (930 mg, 9.8 mmol), TEA (4.7 mL, 33.4 mmol) anddimethyl malonate (1.9 mL, 16.6 mmol) was stirred at RT for 1.5 hfollowed by addition of the above mentioned toluene solution of Compound2. The resulting mixture was stirred at RT for another 1.5 h then conc.HCl (4 mL) was added and stirred for 5 minutes. The mixture wasextracted with EtOAc (30 mL×3), dried (Na₂SO₄), filtered andconcentrated under reduced pressure. To the residue was added 6N HCl (30mL and the mixture was refluxed overnight. The mixture was extractedwith EtOAc (30 mL×3), dried (Na₂SO₄), filtered and concentrated underreduced pressure. The residue was purified via FCC (silica gel,EtOAc/Hexane) to afford Compound 3 as a light yellow solid (1.9 g, 63%yield).

¹H NMR (CDCl3, 400 MHz) δ: 8.16 (d, J=8.0 Hz, 1H), 7.86 (t, d=9.2 Hz,2H), 2.68 (s, 3H) ppm.

b. Synthesis of Compound 4

To a mixture of Compound 3 (1.9 g, 10.4 mmol) in MeOH (20 mL) at −10 Cwas added NaBH₄ (418 mg, 11 mmol) in portions. The mixture was stirredbetween −10 C to 0 C for 20 minutes, diluted with EtOAc (300 mL), washedwith sat. NH₄Cl aqueous solution, brine, dried (Na₂SO₄). Filtered andconcentrated under reduced pressure. The residue was purified via FCC(silica gel, EtOAc/Hexane) to afford Compound 4 as a light yellow oil(1.44 g, 75% yield).

¹H NMR (CDCl₃, 400 MHz) δ: 8.06 (t, J=8.4 Hz, 1H), 7.35 (d, J=11.6 Hz,1H), 7.30 (d, J=11.6 Hz, 1H), 5.01-4.99 (m, 1H), 1.52 (d, J=6.4 Hz, 3H)ppm.

c. Synthesis of Compound 5

To a mixture of Compound 4 (1.44 g, 7.78 mmol), Br-IPM (2.88 g, 9.34mmol), PPh₃ (3.06 g, 11.67 mmol) in THF (60 mL) at 0° C. was added DIAD(2.34 g, 11.67 mmol). The mixture was stirred at 0° C. for 1.5 h,concentrated under reduced pressure and purified via FCC (silica gel,EtOAc/Hexane) to afford Compound 5 as a light yellow oil (1.0 g, 27%yield).

¹H NMR (CDCl₃, 400 MHz) δ: 8.09 (t, J=8.0 Hz, 1H), 8.31 (dd, J=2.4, 13.6Hz, 2H), 5.52-5.60 (m, 1H), 3.54-3.19 (m, 8H), 1.63 (d, J=6.4 Hz, 3H)ppm.

d. Synthesis of Compound 6

A mixture of Compound 5 (1 g, 2.1 mmol) and Ag₂O (3 g) in THF (50 mL)was stirred at 65° C. for 3 h. Filtered and concentrated under reducedpressure. The residue was purified via FCC (silica gel, Acetone/Hexane)to afford Compound 6 as a yellow solid (0.6 g, 90% yield).

¹HNMR (CDCl₃, 400 MHz) δ: 8.08 (t, J=8.0 Hz, 1H), 7.36 (d, J=11.6 Hz,1H), 7.31 (d, J=8.4 Hz, 1H), 5.70-5.67 (m, 1H), 2.25-2.08 (m, 8H), 1.64(d, J=6.4 Hz, 3H) ppm.

e. Preparation of Compound 7

Preparation of Compound 7-2

Ac2O (562 mL, 1.5 eq) was added drop wise to a solution of compound 7-1(150 g, 1.08 mol) in Pyridine (700 mL) at 0° C., stirred at r.t. for 6hrs. Evaporated, poured into ice water, filtered, the filter cake wasdried to give compound 7-2 as a white solid (150 g, 74% yield).

1H NMR (400 MHz, CDCl3): δ ppm 8.00-7.98 (d, J=7.6 Hz, 1H), 8.03 (s,1H), 7.83 (s, 1H), 7.51-7.47 (t, J=8.0 Hz, 1H), 7.36-7.34 (dd, J=8.0 Hz1.2 Hz, 1H), 2.34 (s, 3H).

Preparation of Compound 7-3

To a solution of compound 7-2 (150 g, 833 mmol) in DCM (1500 mL), DMF(15 mL) was added, cooled to 0° C. followed by the addition of oxaylchloride (225 mL, 2.50 mol), stirred at r.t. for 4 hrs. Evaporated, theresidue was dissolved in DCM (1000 mL) cooled to 0° C. followed by theaddition of 2M solution of dimethylamine in THF (900 mL, 1.8 mol),stirred at r.t. for 20 hrs. Quenched with H₂O (1500 mL), extracted withDCM (2000 mL×3), evaporated to give crude compound 7-3 as a pale yellowliquid (137 g, 80% yield). ¹H NMR (400 MHz, CDCl3): δ ppm 7.43-7.39 (t,J=8.0 Hz, 1H), 7.29-7.28 (d, J=7.6 Hz, 1H), 7.17-7.13 (m, 2H), 3.00 (s,6H), 2.32 (s, 3H).

Preparation of Compound 7

To a solution of compound?-3 (137 g, 661 mmol) in MeOH (1000 mL), K2CO3(276 g, 2 mol) was added, stirred at r.t. for 5 hrs. Filtered, thefiltrate was evaporated. The residue was dissolved in H₂O (1000 mL),acdified by 4N HCl to PH6.0, filtered, the filter cake was dried to givecompound 7 as a white solid (60 g, 55% yield).

1H NMR (400 MHz, CDCl3): δ ppm 8.25 (s, 1H), 7.19˜7.15 (d, J=8.0 Hz,1H), 6.96˜6.95 (t, J=2.0 Hz, 1H), 6.84˜6.81 (s, 2H), 3.11 (s, 3H), 2.96(s, 3H).

f. Synthesis of TH 2870

To a mixture of compound 7 in DMF (60 mL) at 0° C. was added NaH (60%,0.508 g, 12.7 mmol) in portions. The mixture was stirred at 0 C for 0.5h before Compound 6 (2 g, 6.35 mmol) was added and then stirred at 0 Cfor 2.5 h. The mixture was diluted with EtOAc (500 mL), washed withbrine (50 mL×3), dried over Na₂SO₄, filtered, concentrated under reducedpressure and purified via FCC (silica gel, Acetone/Hexane) to afford TH2870 as a yellow oil.

Final Purification of TH 2870

TH 2870 as mentioned above was purified via semi-prep HPLC (C18 column,acetonitrile/water). The combined collections were concentrated underreduced pressure to afford a light yellow oil as the final product.Acetonitrile was added to the evaporations as an azeotrope agent toremove water.

¹H NMR (400 MHz, CDCl3): δ ppm 7.98-7.96 (d, J=8.4 Hz, 1H), 7.43-7.39(m, 1H), 7.27˜7.21 (m, 2H), 7.10˜7.06 (m, 3H), 5.62˜5.55 (m, 1H), 3.09(s, 3H), 2.97 (s, 3H), 2.19˜2.00 (m, 8H), 1.58˜1.57 (d, J=6.4 Hz, 3H).MS: m/z 460.8[M+1]+. PLC: 254 nm: 94.8%.

Example 1-D. Alternative Preparation of Compound TH 2870

a. Preparation of Compound 3

Compound 1 (200 g, 1.08 mol) was refluxed in SOCl2 (700 mL) with DMF (10ml) for 3 hrs and then SOCl2 was removed under vacuum. The residue wasdiluted with toluene (400 mL) and was used in the following step withoutfurther purification.

A mixture of MgCl2 (103 g, 1.08 mol), TEA (500 mL, 3.60 mol) anddimethyl malonate (145 g, 1.1 mol) was stirred at RT for 1.5 hrs beforethe above mentioned toluene solution of compound 2 was added drop wise.The resulting mixture was stirred at RT for another 1.5 hrs. Washed withH₂O (2 L), extracted with EtOAc (2 L×5), evaporated, 4N HCl was addeduntil PH6.0 and stirred for 5 minutes. The mixture was extracted withEtOAc (2 L×5), evaporated.

To the residue was added 6N HCl (1500 mL) and the mixture was refluxedovernight.

The mixture was extracted with EtOAc (2 L×5), concentrated, purified bysilica gel column (petroleum ether:EtOAc=20:1) to give compound 3 as ayellow solid (80 g, 41% yield).

b. Preparation of Compound 4

To a mixture of compound 3 (150 g, 824 mol) in MeOH (2 L) at −10° C. wasadded NaBH4 (31.2 g, 824 mmol) in portions. The mixture was stirredbetween −10° C. to 0° C. for 20 minutes, diluted with EtOAc (5 L),washed with sat. NH4Cl aqueous solution, brine, dried over Na2SO4,concentrated. The residue was purified by silica gel column (petroleumether:EtOAc=5:1) to give compound 4 as a yellow oil (90 g, 60% yield).

c. Preparation of Compound 5

To a solution of POCl3 (2 ml, 21.6 mmol) in DCM (20 ml) was addedcompound 4 (2 g, 10.8 mmol), then TEA (3.6 ml, 27 mmol) in DCM (10 ml)was added at −40° C. under N2, stirred at −40° C. for 5 hrs. Then2-Bromoethylamine (17.6 g, 86.8 mmol) was added, TEA (12 ml, 86.8 mmol)in DCM (40 ml) was added slowly into above solution at −40° C., stirredfor 0.5 h. K2CO3 (10%, 10.4 g, 100 ml) was added, stirred at r.t. for 5mins Extracted with DCM (300 ml×3), evaporated, purified by silica gelcolumn (EtOAc) to give compound 5 as a yellow oil (2.3 g, 43% yield).

d. Preparation of Compound 6

A mixture of compound 5 (4 g, 8.42 mmol) and Ag2O (5.85 g, 25.26 mmol)in THF (40 ml) was stirred at 65° C. for 3 hrs, filtered andconcentrated. The residue was purified by silica gel column (EtOAc) togive compound 6 as a yellow oil (2.3 g, 87% yield).

e. Preparation of Compound TH 2870

To a solution of Compound 7 (1.81 g, 10.95 mmol) in DMF (10 ml), NaH(60%, 438 mg, 1095 mmol) was added at 0° C., stirred for 10 mins, thencompound 6 (2.3, 7.3 mmol) in DMF (10 ml) was added, stirred at 0° C.for 30 mins.

Quenched with H2O, extracted with EtOAc (100 ml×5), washed with H₂O (150ml), brine, evaporated, purified by silica gel column (DCM:MeOH=40:1) togive compound TH 2870 as a yellow oil (2.3 g, 69% yield).

Example 1-E

Preparation of TH 2846, TH 2850, TH 2852, TH 2854, TH 2860-TH 2866, TH2871-TH 2878, TH 2880, TH 2881, TH 2883, TH 2887-TH 2893, TH 2895, TH2896, TH 2898-TH 2900, TH 2902, TH 2903, TH 2904, TH 2906, TH 2908, TH2909, TH 2911-TH 2923, TH 2925-TH 2935, TH 2937-TH 2942, TH 2944, TH2949, TH 2952-TH 2958, TH 2960, TH 2961, TH 2966-TH 2971, TH 2974, TH2978, TH 2980, TH 2981, TH 2984, TH 2985, TH 2991-TH 2993, TH 3028-TH3037, TH 3041, TH 3042 and TH 3050.

Compounds TH 2846, TH 2850, TH 2852, TH 2854, TH 2860-TH 2866, TH2871-TH 2878, TH 2880, TH 2881, TH 2883, TH 2887-TH 2893, TH 2895, TH2896, TH 2898-TH 2900, TH 2902, TH 2903, TH 2904, TH 2906, TH 2908, TH2909, TH 2911-TH 2923, TH 2925-TH 2935, TH 2937-TH 2942, TH 2944, TH2949, TH 2952-TH 2958, TH 2960, TH 2961, TH 2966-TH 2971, TH 2974, TH2978, TH 2980, TH 2981, TH 2984, TH 2985, TH 2991-TH 2993, TH 3028-TH3037, TH 3041, TH 3042 and TH 3050 were synthesized using similarsynthetic procedures as described above.

TH 2846

Starting with phenol (140 mg). 1H NMR (CDCl3) δ: 1.57 (d, 3H), 1.92-2.20(M, 8H), 5.85 (m, 1H), 7.0 (d, 2H), 7.15-7.26 (dd, 2H), 7.38 (t, 2H),7.70 (d, 1H). 31.2.

TH 2850

1H NMR (CDCl3, 400 MHz) δ 7.95 (d, 1H), 7.39 (t, 2H), 7.18 (m, 2H), 7.05(d, 2H), 7.99 (s, 1H), 5.10 (d, 2H), 2.18-2.12 (m, 8H).

TH 2852

1H NMR (CDCl3, 400 MHz) δ 8.40 (bs, 1H), 8.0 (bs, 1H), 7.35 (bs, 4H),7.20 (s, 1H), 5.12 (bs, 1H), 2.18-2.12 (bs, 8H), 1.6 (bd, 3H).

TH 2854

1H NMR (CDCl3, 400 MHz) δ: 8.00 (d, J=8.4 Hz, 1H), 7.89 (d, J=8.2 Hz,1H), 7.67 (s, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.27-7.25 (m, 2H), 7.06 (d,J=1.2 Hz, 1H), 5.62-5.60 (m, 1H), 4.37 (q, J=6.8 Hz, 2H), 2.18-2.00 (m,8H), 1.39 (t, J=6.8 Hz, 3H).

TH 2855

1H NMR (CDCl3, 400 MHz) δ: 7.96 (d, J=8.4 Hz, 1H), 7.27-7.05 (m, 3H),6.60-6.32 (m, 3H), 5.64-5.59 (m, 1H), 2.96 (s, 6H), 2.20-2.00 (m, 8H),1.58 (d, J=6.4 Hz, 3H).

TH 2860

Starting with 4-Chloro-phenol (60 mg). 1H NMR (CDCl3) δ: 1.58 (d, 3H),1.97-2.25 (m, 8H), 5.59 (m, 1H), 6.95 (d, 2H), 7.05 (d, 1H), 7.24 (dd,1H), 7.35 (d, 2H), 7.96 (d, 1H). 31PNMR (CDCl3) δ: 31.3.

TH 2861

Starting with 4-Fluorophenol (50 mg). 1H NMR (CDCl3) δ: 1.55 (d, 3H),1.92-2.15 (m, 8H), 5.54 (m, 1H), 6.95-7.16 (m, 5H), 7.20 (dd, 1H), 7.94(d, 1H). 31PNMR (CDCl3) δ: 31.3.

TH 2862

Starting with 2-Chloro-phenol (60 mg). 1H NMR (CDCl3) δ: 1.55 (d, 3H),1.95-2.20 (m, 8H), 5.56 (m, 1H), 6.81 (d, 1H), 7.10 (d, 1H), 7.13-7.35(m, 3H), 7.50 (dd, 1H), 8.0 (d, 1H). 31PNMR (CDCl3) δ: 31.3.

TH 2863

Starting with 2,4-difluoro-phenol (60 mg). 1H NMR (CDCl3) δ: 1.54 (d,3H), 1.91-2.20 (m, 8H), 5.56 (m, 1H), 6.85-7.05 (m, 3H), 7.10-7.22 (m,2H), 7.98 (d, 1H). 31PNMR (CDCl3) δ: 31.4.

TH 2864

Starting with 2,4-dichloro-phenol (73 mg). 1H NMR (CDCl3) δ: 1.55 (d,3H), 1.95-2.25 (m, 8H), 5.57 (m, 1H), 6.86 (d, 1H), 7.0 (d, 1H),7.20-7.30 (m, 2H), 7.48 (dd, 1H), 7.99 (d, 1H). 31PNMR (CDCl3) δ: 31.4.

TH 2865

Starting with 2-Fluorophenol (50 mg). 1H NMR (CDCl3) δ: 1.54 (d, 3H),1.95-2.25 (m, 8H), 5.57 (m, 1H), 6.89 (d, 1H), 7.10-7.30 (m, 5H), 7.99(d, 1H). 31PNMR (CDCl3) δ: 31.3.

TH 2866

Starting 1,3-benzodioxol-5-ol (62 mg). 1H NMR (CDCl3) δ: 1.55 (d, 3H),1.95-2.25 (m, 8H), 5.56 (m, 1H), 6.0 (s, 2H), 6.50 (dd, 1H), 6.59 (d,1H), 6.78 (d, 1H), 6.99 (s, 1H), 7.13 (d, 1H), 7.96 (d, 1H). 31PNMR(CDCl3) δ: 31.3.

TH 2871

Starting with 3-(trifluoromethyl)phenol (73 mg). 1H NMR (CDCl3) δ: 1.58(d, 3H), 1.95-2.25 (m, 8H), 5.59 (m, 1H), 7.10 (s, 1H), 7.15-7.50 (m,5H), 7.99 (d, 1H). 31PNMR (CDCl3) δ: 31.5.

TH 2872

Starting with 4-Cyanophenol (54 mg) 1H NMR (CDCl3) δ: 1.58 (d, 3H),1.97-2.25 (m, 8H), 5.65 (m, 1H), 7.0 (d, 2H), 7.21 (d, 1H), 7.38 (dd,1H), 7.65 (d, 2H), 8.05 (d, 1H). 31PNMR (CDCl3) δ: 31.5.

TH 2873

Starting material with 4-Methoxyphenol (56 mg). 1H NMR (CDCl3) δ: 1.54(d, 3H), 1.95-2.19 (m, 8H), 3.83 (s, 3H), 5.53 (m, 1H), 6.90-6.97 (m,3H), 7.0 (d, 2H), 7.13 (dd, 1H), 7.93 (d, 1H). 31PNMR (CDCl3) δ: 31.2.

TH 2874

1H NMR (CDCl3, 400 MHz) δ 8.13-8.11 (dd, 1H), 7.61 (t, 1H), 7.44 (m,2H), 7.30 (t, 1H), 6.62-6.59 (dd, 1H), 6.33 (t, 1H), 5.72 (m, 1H),2.18-2.12 (m, 8H), 1.60 (m, 3H).

TH 2875

1H NMR (CDCl3, 400 MHz) δ 8.08 (d, 1H), 7.65 (d, 1H), 7.49 (s, 1H), 7.3(m, 2H), 6.63 (d, 1H), 6.30 (t, 1H), 5.12 (d, 2H), 2.18-2.12 (m, 8H).

TH 2876

1H NMR (CDCl3, 400 MHz) δ 8.08 (d, 2H), 7.40-7.00 (m, 5H), 5.12 (d, 2H),4.40 (q, 2H), 2.18-2.12 (m, 8H), 1.60 (t, 3H).

TH 2877

1H NMR (CDCl3, 400 MHz) δ 8.43-8.38 (m, 2H), 7.98 (d, 2H), 7.35 (d, 1H),7.33-7.25 (m, 2H), 7.07 (s, 1H), 5.12 (d, 1H), 2.18-2.12 (m, 8H).

TH 2878

1H NMR (CDCl3) δ 8.25 (d, 1H), 7.7 (d, 1H), 7.65 (s, 1H), 7.52-7.46 (m,1H), 7.3-7.1 (m, 2H), 6.7-6.6 (m, 1H), 5.8-5.7 (m, 1H), 2.25-2 (m, 8H),1.67 (d, 3H).

TH 2880

1H NMR (CDCl3) δ 8.05-7.8 (m, 3H), 7.4-7.3 (m, 2H), 7.1-6.9 (m, 2H),5.75 (s, 2H), 5.7-5.5 (m, 1H), 2.2-1.9 (m, 8H), 1.56 (d, 3H).

TH 2881

1H NMR (CDCl3) δ 8.05-7.7 (m, 3H), 7.4-7.3 (m, 1H), 7.2 (s, 1H), 7.2-7.0(m, 2H), 5.7-5.5 (m, 1H), 2.72 (s, 6H), 2.2-1.9 (m, 8H), 1.61 (d, 3H).

TH 2883

Starting with 4-(methylsulfonyl)phenol (78 mg). 1H NMR (CDCl3) δ: 1.62(d, 3H), 2.01-2.22 (m, 8H), 3.07 (s, 3H), 5.67 (m, 1H), 7.09 (d, 2H),7.24 (s, 1H), 7.38 (d, 1H), 7.92 (d, 2H), 8.05 (d, 1H). 31PNMR (CDCl3)δ: 31.5.

TH 2884

1HNMR (CDCl3, 400 MHz) δ: 8.00-7.93 (m, 1H), 7.62-7.60 (m, 1H),7.48-7.34 (m, 2H), 7.20-7.11 (m, 2H), 5.52-5.48 (m, 1H), 2.94-2.83 (m,3H), 2.14-1.95 (m, 8H), 1.55 (d, J=6.4 Hz, 3H).

TH 2885

1HNMR (CDCl3, 400 MHz) δ: 7.94-7.91 (m, 1H), 7.41-7.36 (m, 2H),7.28-7.18 (m, 2H), 7.01-6.94 (m, 2H), 5.56-5.53 (m, 1H), 3.06-2.88 (m,6H), 2.15-1.96 (m, 8H), 1.54-1.52 (m, 3H).

TH 2887

1H NMR (CDCl3, 400 MHz) δ 8.08 (d, 1H), 7.92 (d, 2H), 7.35 (d, 1H), 7.20(s, 1H), 7.07 (d, 2H), 5.12 (d, 1H), 2.18-2.12 (m, 8H).

TH 2888

1H NMR (CDCl3, 400 MHz) δ 7.94 (d, 1H), 7.15 (d, 1H), 6.98 (s, 1H), 6.74(d, 1H), 6.61 (d, 1H), 6.54 (dd, 1H), 6.02 (s, 2H), 5.12 (d, 1H),2.18-2.12 (m, 8H).

TH 2889

1H NMR (CDCl3, 400 MHz) δ 7.98 (d, 1H), 7.42 (t, 1H), 7.23 (m, 2H), 7.07(m, 3H), 5.13 (d, 2H), 3.09 (s, 3H), 2.98 (s, 3H), 2.18-2.12 (m, 8H).

TH 2890

1H NMR (CDCl3, 400 MHz) δ 8.31 (d, 1H), 8.00 (d, 1H), 7.35-7.23 (m, 3H),7.01 (s, 1H), 5.14 (d, 2H), 2.58 (s, 3H), 2.20-2.10 (m, 8H).

TH 2891

1H NMR (CDCl3, 400 MHz) δ 8.27 (d, 1H), 7.97 (d, 1H), 7.35-7.23 (m, 3H),7.01 (s, 1H), 5.80 (m, 1H), 2.56 (s, 3H), 2.20-2.10 (m, 8H), 1.55 (d,3H).

TH 2892

1H NMR (CDCl3, 400 MHz) δ 7.97 (d, 1H), 7.94 (bs, 1H), 7.48 (m, 1H),7.26 (d, 1H), 7.03 (s, 1H), 6.97-6.94 (dd, 1H), 5.14 (d, 2H), 2.20-2.10(m, 8H).

TH 2893

1H NMR (CDCl3, 400 MHz) δ 7.97 (d, 1H), 7.94 (bs, 1H), 7.51 (m, 1H),7.29 (d, 1H), 7.08 (s, 1H), 6.97-6.94 9 dd, 1H), 5.60 (m, 1H), 2.20-2.10(m, 8H), 1.66-1.58 (d, 3H).

TH 2895

1H NMR (CDCl3) δ: 1.95-2.18 (m, 8H), 3.83 (s, 3H), 5.09 (d, 2H), 6.84(d, 2H), 6.89-6.96 (m, 3H), 7.13 (d, 1H), 7.94 (d, 1H). 31PNMR (CDCl3)δ: 32.2.

TH 2896

1H NMR (CDCl3) δ: 2.05-2.22 (m, 8H), 5.08 (d, 2H), 6.71 (d, 2H),6.88-6.93 (m, 3H), 7.10 (d, 1H), 7.93 (d, 1H). 31PNMR (CDCl3) δ: 32.2.

TH 2898

1H NMR (CDCl3) δ 8.05-7.98 (m, 3H), 7.87 (d, 1H), 7.34 (d, 1H), 7.28 (d,1H), 7.15 (s, 1H), 7.1 (d, 2H), 5.7-5.5 (m, 1H), 2.2-1.98 (m, 8H), 1.61(d, 3H).

TH 2899

1H NMR (CDCl3) δ 8.1-7.9 (m, 3H), 7.85 (d, 1H), 7.33 (dd, 1H), 7.28 (dd,1H), 7.15-7.05 (m, 3H), 5.16 (d, 2H), 2.2-2.08 (m, 8H).

TH 2900

1H NMR (CDCl3) δ 8.98 (s, 1H), 8.15 (d, 1H), 8.01 (d, 1H), 7.61 (s, 1H),7.3-7.2 (m, 2H), 7.09 (s, 1H), 5.65-5.55 (m, 1H), 2.2-1.96 (m, 8H), 1.58(d, 3H).

TH 2902

1H NMR (CDCl3) δ 8.05 (d, 1H), 7.87 (d, 2H), 7.37 (d, 1H), 7.23 (s, 1H),7.09 (d, 2H), 5.7-5.5 (m, 1H), 4.5-4.3 (m, 1H), 2.7 (d, 3H), 2.22-2.02(m, 8H), 1.63 (d, 3H).

TH 2903

1H NMR (CDCl3) δ 8.05 (d, 1H), 7.87 (d, 2H), 7.36 (d, 1H), 7.21 (s, 1H),7.09 (d, 2H), 5.21 (d, 2H), 4.5-4.4 (m, 1H), 2.7 (d, 3H), 2.25-2.1 (m,8H).

TH 2904

1H NMR (CDCl3) δ 8.06 (d, 2H), 8.01 (d, 1H), 7.71 (s, 1H), 7.3-7.2 (m,2H), 7.15 (s, 1H), 7.09 (d, 2H), 5.65-5.55 (m, 1H), 2.2-1.96 (m, 8H),1.59 (d, 3H).

TH 2906

1H NMR (CDCl3, 400 MHz) δ: 8.01 (s, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.40(t, J=8.0 Hz, 2H), 7.21 (t, J=7.2 Hz, 1H), 7.06 (d, J=8.0 Hz, 2H), 7.01(d, J=8.4 Hz, 1H)-5.18 (d, J=8.0 Hz, 2H), 2.25-2.17 (m, 8H).

TH 2908

1H NMR (CDCl3, 400 MHz) δ: 8.00 (d, J=8.4 Hz, 1H), 7.47 (d, J=8.4 Hz,2H), 7.28 (d, J=8.0 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J=8.4 Hz, 2H),5.60-5.58 (m, 1H), 3.12 (s, 3H), 3.04 (s, 3H), 2.19-2.02 (m, 8H), 1.58(d, J=6.4 Hz, 3H).

TH 2909

1H NMR (CDCl3, 400 MHz) δ: 8.00 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.4 Hz,2H), 7.30-7.28 (m, 1H), 7.14 (s, 1H), 7.04 (d, J=4.8 Hz, 2H), 6.14 (br,1H), 5.64-5.59 (m, 1H), 3.02 (d, J=5.6 Hz, 3H), 2.20-2.00 (m, 8H), 1.58(d, J=6.4 Hz, 3H).

TH 2911

Starting with 4-(methylsulfonyl)phenol (120 mg). 1H NMR (CDCl3) δ:2.10-2.28 (m, 8H), 3.08 (s, 3H), 5.23 (d, 2H), 7.11 (d, 2H), 7.24 (s,1H), 7.39 (d, 2H), 7.93 (d, 2H), 8.07 (d, 1H). 31PNMR (CDCl3) δ: 32.3.

TH 2912

Starting with N-(4-Hydroxy-phenyl)-methanesulfonamide (115 mg). 1H NMR(CDCl3) δ: 1.58 (d, 3H), 2.0-2.22 (m, 8H), 3.0 (s, 3H), 5.58 (m, 1H),6.97-7.11 (m, 3H), 7.22-7.32 (m, 3H), 7.94 (d, 1H). 31PNMR (CDCl3) δ:31.5.

TH 2913

Starting with N-(4-Hydroxy-phenyl)-trifluoromethanesulfonamide (145 mg).1H NMR (CDCl3) δ: 1.57 (d, 3H), 2.01-2.22 (m, 8H), 2.97 (s, 3H), 5.58(m, 1H), 6.98 (d, 2H), 7.04 (s, 1H), 7.23 (d, 1H), 7.29 (d, 2H), 7.97(d, 1H). 31PNMR (CDCl3) δ: 31.5. 19FNMR (CDCl3) δ: −76.0.

TH 2914

1H NMR (CDCl3) δ 8.15 (s, 1H), 8.0 (d, 1H), 7.62 (d, 1H), 7.43 (d, 1H),7.23 (d, 1H), 7.18 (dd, 1H), 7.03 (s, 1H), 5.62-5.52 (m, 1H), 2.2-1.96(m, 8H), 1.56 (d, 3H).

TH 2915

1H NMR (CDCl3) δ 8.16 (s, 1H), 8.01 (d, 1H), 7.63 (d, 1H), 7.46 (d, 1H),7.23 (d, 1H), 7.26-7.16 (m, 2H), 7.02 (s, 1H), 5.14 (d, 1H), 2.2-1.96(m, 8H).

TH 2916

1H NMR (CDCl3) δ 8.04 (d, 1H), 7.68 (d, 2H), 7.36 (d, 1H), 7.19 (s, 1H),7.08-7.02 (m, 2H), 7.02-6.94 (m, 4H), 5.7-5.62 (m, 1H), 2.22-2.02 (m,8H), 1.61 (d, 3H).

TH 2917

1H NMR (CDCl3) δ 8.0 (d, 1H), 7.98 (s, 1H), 7.73 (d, 1H), 7.23 (d, 1H),7.05 (d, 2H), 6.9 (d, 1H), 5.62-5.52 (m, 1H), 4.03 (d, 3H), 2.2-1.94 (m,8H), 1.56 (d, 3H).

TH 2918

1H NMR (CDCl3) δ 8.01 (d, 1H), 7.99 (s, 1H), 7.74 (d, 1H), 7.23 (d, 1H),7.04 (s, 2H), 6.91 (dd, 1H), 5.62-5.13 (d, 2H), 4.03 (d, 3H), 2.2-2.02(m, 8H).

TH 2919

1H NMR (CDCl3) δ 7.97 (d, 1H), 7.95 (s, 1H), 7.45 (d, 1H), 7.37 (d, 1H),7.22-7.14 (m, 2H), 6.94 (s, 1H), 5.62-5.5 (m, 1H), 4.12 (d, 3H),2.16-1.92 (m, 8H), 1.53 (d, 3H).

TH 2920

1H NMR (CDCl3) δ 7.98 (d, 1H), 7.92 (s, 1H), 7.47 (d, 1H), 7.42 (d, 1H),7.22-7.1 (m, 2H), 6.95 (s, 1H), 5.6-5.4 (m, 1H), 3.9 (d, 3H), 2.16-1.94(m, 8H), 1.52 (d, 3H).

TH 2921

1H NMR (CDCl3) δ 7.98 (d, 1H), 7.92 (s, 1H), 7.48 (s, 1H), 7.43 (d, 1H),7.22-7.1 (m, 2H), 6.94 (s, 1H), 5.6-5.07 (d, 2H), 3.9 (d, 3H), 2.16-2.05(m, 8H), 1.52 (d, 3H).

TH 2922

1H NMR (CDCl3, 400 MHz) δ 8.08 (d, 1H), 8.04 (dd, 1H), 7.77 (t, 1H),7.57 (t, 1H), 7.40 (dd, 2H), 7.21 (s, 1H), 5.22 (d, 2H), 2.23-2.12 (m,8H).

TH 2923

1H NMR (CDCl3, 400 MHz) δ: 8.01 (d, J=8.4 Hz, 1H), 7.84 (d, J=8.0 Hz,2H), 7.31 (dd, J=1.2, 8.4 Hz, 1H), 7.14 (d, J=1.2 Hz, 1H), 7.02 (d,J=8.4 Hz, 2H), 5.62-5.60 (m, 1H), 2.18-2.00 (m, 8H), 1.58 (d, J=6.8 Hz,3H).

TH 2924

1H NMR (CDCl3, 400 MHz) δ: 8.0 (d, J=8.4 Hz, 1H), 7.68 (d, J=8.0 Hz,1H), 7.50 (t, J=8.4 Hz, 1H), 7.41 (s, 1H), 7.34-7.20 (m, 3H), 5.60-5.50(m, 1H), 2.20-2.10 (m, 4H), 2.04-1.96 (m, 4H), 1.59 (d, J=6.8 Hz, 3H).

TH 2925

1H NMR (CDCl3, 400 MHz) δ: 9.05 (s, 1H), 8.50 (s, 2H), 8.07 (d, J=8.4Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.23 (s, 1H), 5.64-5.60 (m, 1H),2.22-2.05 (m, 8H), 1.60 (d, J=6.4 Hz, 3H).

TH 2926

Starting with N-(4-Hydroxy-phenyl)-chloromethanesulfonamide (133 mg). 1HNMR (CDCl3) δ: 2.08-2.21 (m, 8H), 4.48 (s, 2H), 5.16 (d, 2H), 7.03 (d,2H), 7.07 (s, 1H), 7.24 (d, 1H), 7.34 (d, 2H), 7.98 (d, 1H). 31PNMR(CDCl3) δ: 32.1.

TH 2927

Starting with 4-Cyanophenol (144 mg). 1H NMR (CDCl3) δ: 2.12-2.28 (m,8H), 5.23 (d, 2H), 7.05 (d, 2H), 7.23 (s, 1H), 7.39 (d, 1H), 7.67 (d,2H), 8.07 (d, 1H). 31PNMR (CDCl3) δ: 32.3.

TH 2928

1H NMR (CDCl3) δ 8.01 (d, 1H), 7.82 (d, 1H), 7.55 (d, 1H), 7.25 (dd,1H), 7.15 (dd, 1H), 7.08 (s, 1H), 5.6-5.4 (m, 1H), 2.85 (d, 3H),2.18-1.94 (m, 8H), 1.56 (d, 3H).

TH 2929

1H NMR (CDCl3) δ 8.01 (d, 1H), 7.83 (d, 1H), 7.57 (d, 1H), 7.24 (dd,1H), 7.15 (dd, 1H), 7.06 (s, 1H), 5.6-5.12 (d, 2H), 2.85 (d, 3H),2.2-2.05 (m, 8H).

TH 2930

1H NMR (CDCl3) δ 7.99 (d, 1H), 7.95 (d, 1H), 7.5 (d, 1H), 7.23 (d, 1H),7.18 (dd, 1H), 7.05 (s, 1H), 5.6-5.5 (m, 1H), 2.85 (d, 3H), 2.18-1.94(m, 8H), 1.57 (d, 3H).

TH 2931

1H NMR (CDCl3) δ 7.99 (d, 1H), 7.94 (d, 1H), 7.5 (d, 1H), 7.26-7.16 (m,2H), 7.02 (s, 1H), 5.12 (d, 2H), 2.84 (d, 3H), 2.16-2.02 (m, 8H).

TH 2932

1H NMR (CDCl3) δ 8.02 (d, 1H), 7.28-7.16 (m, 2H), 7.07 (t, 2H), 6.87 (s,1H), 5.6-5.5 (m, 1H), 2.18-1.96 (m, 8H), 1.55 (d, 3H).

TH 2933

1H NMR (CDCl3) δ 8.94 (d, 1H), 8.92-8.88 (m, 1H), 8.42 (d, 1H), 8.12 (d,1H), 7.63 (d, 1H), 7.58 (dd, 1H), 7.43 (dd, 1H), 7.34 (d, 1H), 5.7-5.6(m, 1H), 2.22-2.0 (m, 8H), 1.63 (d, 3H).

TH 2934

1H NMR (CDCl3, 400 MHz) δ 8.25-8.23 (m, 2H), 8.08 (d, 2H), 7.43-7.40(dm, 1H), 7.27 (m, 1H), 7.20-7.07 (dd, 2H), 5.24 (d, 2H), 2.21-2.15 (m,8H).

TH 2935

1H NMR (CDCl3, 400 MHz) δ 7.42-7.40 (dd, 2H), 7.42 (d, 2H), 7.27 (s,1H), 7.20-7.07 (2, 2H), 5.66 (m, 1H), 2.18-2.12 (m, 8H), 1.6 (d, 3H).

TH 2937

1H NMR (CDCl3, 400 MHz) δ 7.98 (d, 1H), 7.61 (d, 1H), 7.43 (t, 1H), 7.34(m, 1H), 7.21 (d, 2H), 7.14 (s, 1H), 6.95 (bs, 1H), 5.17 (d, 2H), 2.9(2, 3H), 2.18-2.12 (m, 8H).

TH 2938

1H NMR (CDCl3, 400 MHz) δ 7.93 (d, 1H), 7.40 (m, 2H), 7.23 (m, 1H), 7.19(d, 1H), 6.98 (d, 1H), 6.98 (s, 1H), 5.08 (d, 2H), 3.02 (s, 3H), 2.94(s, 3H), 2.18-2.12 (m, 8H).

TH 2939

1H NMR (CDCl3, 400 MHz) δ 7.91 (m, 1H), 7.44 (m, 2H), 7.18 (m, 2H), 6.86(d, 2H), 6.60 (bs, 1H), 5.18 (d, 2H), 3.47 (s, 3H), 2.18-2.12 (m, 8H).

TH 2940

1H NMR (CDCl3, 400 MHz) δ 8.02 (d, 1H), 7.79 (d, 2H), 7.29 (d, 1H), 7.12(s, 1H), 7.04 (d, 2H), 6.25 (s, 1H), 5.20 (d, 2H), 3.02 (d, 3H),2.18-2.12 (m, 8H).

TH 2941

1H NMR (CDCl3, 400 MHz) δ 8.02 (s, 1H), 8.00 (d, 1H), 7.47 (d, 2H), 7.08(s, 1H), 7.47 (d, 2H), 5.15 (d, 2H), 3.11 (s, 3H), 3.03 (s, 3H),2.18-2.12 (m, 8H).

TH 2942

1H NMR (CDCl3, 400 MHz) δ 8.08 (d, 1H), 8.03 (d, 1H), 7.75 (t, 1H), 7.38(dt, 1H), 7.22 (dd, 2H), 7.21 (s, 1H), 5.68 (m, 1H), 2.23-2.12 (m, 8H),1.54 (d, 3H).

TH 2944

1H NMR (CDCl3, 400 MHz) δ: 8.11 (d, J=10.8 Hz, 1H), 7.61 (dd, J=2.0,11.2 Hz, 1H), 7.50 (d, J=1.6 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 6.38 (d,J=7.2 Hz, 1H), 5.76-5.71 (m, 1H), 2.27-2.07 (m, 8H), 1.66 (d, J=10.4H,3H).

TH 2945

1H NMR (CDCl3, 400 MHz) δ: 9.00 (s, 1H)-8.05 (d, J=11.2 1H), 7.98 (d,J=11.2 Hz, 1H), 7.66 (t, J=10.4 Hz, 1H), 7.48 (dd, J=6.0, 11.6 Hz, 1H),7.30 (d, J=1.6 Hz, 1H), 7.26 (s, 1H), 7.06 (d, J=1.6 Hz, 1H), 7.0 (d,J=10.4 Hz, 1H), 5.62-5.60 (m 1H), 2.18-1.92 (m, 8H), 1.57 (d, J=8.8 Hz,3H).

TH 2946

Starting with N-(4-Hydroxy-phenyl)-methanesulfonamide (150 mg). 1H NMR(CDCl3) δ: 2.11-2.20 (m, 8H), 3.02 (s, 3H), 5.16 (d, 2H), 7.02-7.07 (m,3H), 7.23-7.29 (m, 3H), 7.99 (d, 1H). 31PNMR (CDCl3) δ: 32.1.

TH 2947

Starting with 3-Hydroxy-2-phenylacrylonitrile (88 mg). 1H NMR (CDCl3) δ:1.66 (d, 3H), 2.03-2.26 (m, 8H), 5.65 (m, 1H), 7.29 (dd, 1H), 7.47-7.62(m, 3H), 7.72 (d, 1H), 7.90 (d, 2H), 8.01 (d, 1H).

TH 2948

Starting with 2-Hydroxyimino-2-phenylacetonitrile (97 mg). 1H NMR(CDCl3) δ: 2.18-2.32 (m, 8H), 5.28 (m, 1H), 7.31 (dd, 1H), 7.51-7.64 (m,3H), 7.76 (d, 1H), 7.94 (d, 2H), 8.06 (d, 1H).

TH 2949

Starting with 1-Phenyl-1-ethanone oxime (90 mg). 1H NMR (CDCl3) δ:2.16-2.29 (m, 8H), 2.59 (s, 3H), 5.22 (d, 1H), 7.13 (dd, 1H), 7.44-7.49(m, 3H), 7.75-7.79 (m, 2H), 7.91 (d, 1H), 8.02 (d, 1H).

TH 2950

Starting with 3-(methylsulfonyl)phenol (78 mg). ¹HNMR (CDCl₃) δ: 1.60(d, 3H), 2.01-2.20 (m, 8H), 3.06 (s, 3H), 5.63 (m, 1H), 7.18 (S, 1H),7.30-7.38 (m, 2H), 7.50 (S, 1H), 7.59 (t, 1H), 7.73 (d, 1H), 8.02 (d,1H). ³¹PNMR (CDCl₃) δ: 31.5.

TH 2951

Starting with 3-(methylsulfonyl)phenol (113 mg). ¹HNMR (CDCl₃) δ:2.12-2.22 (m, 8H), 3.07 (s, 3H), 5.19 (d, 2H), 7.18 (S, 1H), 7.30-7.38(m, 2H), 7.52 (s, 1H), 7.60 (t, 1H), 7.73 (d, 1H), 8.04 (d, 1H). ³¹PNMR(CDCl3) δ: 32.3.

TH 2952

1H NMR (CDCl3, 400 MHz) δ: 8.98 (s, 1H), 8.15 (d, J=12.0 Hz, 1H), 8.05(t, J=8.8 Hz, 2H), 7.50 (dd, J=3.6, 12.0 Hz, 1H), 7.42 (dd, J=6.0, 11.6Hz, 1H), 7.32 (dd, J=3.6, 8.0 Hz, 1H), 7.28-7.27 (m, 2H), 7.15 (d, J=2.0Hz, 1H), 5.62-5.60 (m, 1H), 2.20-1.94 (m, 8H), 1.59 (d, J=8.8 Hz, 3H).

TH 2954

1H NMR (CDCl3, 400 MHz) δ: 8.11 (d, J=10.0 Hz, 1H0, 9.02 (d, J=11.2 Hz,1H), 7.91 (d, J=10.0 Hz, 1H), 7.74 (d, J=11.2 Hz, 1H), 7.60-7.50 (m,1H), 7.45 (t, J=10.0 Hz, 1H), 7.18 (dd, J=2.0, 11.6 Hz, 1H), 7.06 (d,J=10.0 Hz, 1H), 6.90 (d, J=1.2 Hz, 1H), 5.60-5.50 (m, 1H), 2.12-2.00 (m,4H), 1.96-1.84 (m, 4H), 1.52 (d, J=8.8 Hz, 3H).

TH 2955

1H NMR (CDCl3, 400 MHz) δ: 8.02 (d, J=11.2 Hz, 1H), 7.92-7.85 (m, 2H),7.74 (d, J=10.0 Hz, 1H), 7.54-7.46 (m, 2H), 7.49 (d, J=3.2 Hz, 1H),7.30-7.22 (m, 2H), 7.08 (d, J=1.6 Hz, 1H), 5.62-5.46 (m, 1H), 2.18-1.92(m, 8H), 1.57 (d, J=8.8 Hz, 3H).

TH 2956

1H NMR (CDCl3, 400 MHz) δ: 8.82 (d, J=4.0 Hz, 1H), 8.14 (d, J=11.2 Hz,1H), 8.07 (d, J=9.6 Hz, 1H), 7.75-7.55 (m, 4H), 7.33 (dd, J=2.0, 11.2Hz, 1H), 7.15 (d, J=2.0 Hz, 1H), 5.62-5.58 (m, 1H), 2.20-1.96 (m, 8H),1.60 (d, J=9.2 Hz, 3H).

TH 2957

1H NMR (CDCl3, 400 MHz) δ: 8.82 (s, 1H), 8.17 (dd, J=2.0, 11.2 Hz, 1H),8.08 (d, J=10.8 Hz, 1H), 7.89-7.86 (m, 1H), 7.43-7.33 (m, 4H), 7.27-7.26(m, 1H), 5.62-5.58 (m, 1H), 2.22-2.00 (m, 8H), 1.62 (d, J=8.4 Hz, 3H).

TH 2958

1H NMR (CDCl3, 400 MHz) δ: 8.00 (d, J=11.6 Hz, 1H), 7.63-7.56 (m, 4H),7.46 (t, J=9.6 Hz, 2H), 7.38 (d, J=9.6 Hz, 1H), 7.21 (d, J=10.8 Hz, 1H),7.13 (d, J=12.0 Hz, 2H), 7.09 (s, 1H), 5.16 (d, J=10.8 Hz, 2H),2.24-2.08 (m, 8H).

TH 2960

1H NMR (CDCl3, 400 MHz) δ 7.98 (dd, 1H), 7.75 (d, 1H), 7.60 (d, 1H),7.43 (t, 2H), 7.24 (t, 1H), 7.04 (d, 2H), 5.42 (d, 2H), 2.23-2.12 (m,8H).

TH 2961

Starting with 1-Phenyl-1-ethanone oxime (81 mg). 1H NMR (CDCl3) δ: 1.64(d, 3H), 2.16-2.29 (m, 8H), 2.56 (s, 3H), 5.62 (m, 1H), 7.13 (dd, 1H),7.44-7.49 (m, 3H), 7.75-7.79 (m, 2H), 7.92 (d, 1H), 8.04 (d, 1H).

TH 2966

1H NMR (CDCl3, 400 MHz) δ: 8.09 (d, J=10.4 Hz, 1H), 8.03 (d, J=11.2 Hz,1H), 7.92 (d, J=10.0 Hz, 1H), 7.75 (d, J=10.0 Hz, 1H), 7.60-7.43 (m,3H), 7.16 (d, J=11.2 Hz, 1H), 7.09 (d, J=10.0 Hz, 1H), 6.86 (s, 1H),5.05 (d, J=10.0 Hz, 2H), 2.10-1.90 (m, 8H).

TH 2967

1H NMR (CDCl3, 400 MHz) δ: 9.00 (dd, J=2.0, 6.0 Hz, 1H), 8.52 (d, J=11.2Hz, 1H), 8.06 (d, J=11.2 Hz, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.67 (t,J=10.4 Hz, 2H), 7.48 (dd, J=5.6, 11.2 Hz, 1H), 7.26 (s, 1H), 7.05 (d,J=10.4 Hz, 1H), 5.12 (d, J=10.8 Hz, 2H), 2.20-2.02 (m, 8H).

TH 2968

1H NMR (CDCl3, 400 MHz) δ: 8.02 (d, J=10.8 Hz, 1H), 7.94-7.82 (m, 2H),7.78-7.72 (m, 1H), 7.54-7.38 (m 3H), 7.32-7.20 (m, 2H), 7.05 (d, J=2.4Hz, 1H), 5.13 (d, J=10.4 Hz, 2H), 2.12-2.05 (m, 8H).

TH 2969

1H NMR (CDCl3, 400 MHz) δ: 8.83 (d, J=4.0 Hz, 1H), 8.14 (d, J=11.2 Hz,1H), 8.07 (d, J=10.8 Hz, 1H), 7.76-7.52 (m, 4H), 7.32 (d, J=10.8 Hz,1H), 7.13 (s, 1H), 5.18 (d, J=10.4 Hz, 2H), 2.16-2.09 (m, 8H).

TH 2970

1H NMR (CDCl3, 400 MHz) δ: 8.84 (d, J=4.0 Hz, 1H), 8.18 (d, J=10.0 Hz,1H), 8.08 (d, J=11.6 Hz, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.40-7.33 (m, 4H),7.26 (s, 1H), 5.20 (d, J=10.4 Hz, 2H), 2.23-2.10 (m, 8H).

TH 2971

1H NMR (CDCl3, 400 MHz) δ: 8.96 (d, J=4.0 Hz, 1H), 8.15 (d, J=12.0H 5.17(d, J=10.8 Hz, 1H), 8.09-8.03 (m, 2H), 7.51 (dd, J=3.6, 12.0 Hz, 1H),7.43 (dd, J=5.6, 11.2 Hz, 1H), 7.33 (d, J=3.2 Hz, 1H), 7.31-7.27 (m,1H), 7.13-7.12 (m, 1H), 5.17 (d, J=10.8 Hz, 2H), 2.16-2.08 (m, 8H).

TH 2972

1H NMR (CDCl3, 400 MHz) δ: 7.96-7.93 (m, 1H), 7.41-7.36 (m, 1H),7.26-7.23 (m, 1H), 7.18-7.15 (m, 1H), 7.10-7.09 (m, 1H), 7.05-7.02 (m,2H), 5.58-5.54 (m, 1H), 3.80-3.40 (m, 8H), 2.10-1.98 (m, 8H), 1.56 (d,J=6.4 Hz, 3H).

TH 2973

1H NMR (CDCl3, 400 MHz) δ: 7.98 (d, J=8.4 Hz, 1H), 7.42 (t, J=8.0 Hz,1H), 7.28-7.26 (m, 1H), 7.22-7.20 (m, 1H), 7.18-7.03 (m, 3H), 5.16-5.14(m, 1H), 3.80-3.35 (m, 8H), 2.18-2.10 (m, 8H), 1.58 (d, J=6.4 Hz, 3H).

TH 2974

1H NMR (CDCl3, 400 MHz) δ 7.93 (d, 1H), 7.32-7.20 (m, 8H), 7.02 (d, 2H),6.96 (s, 1H), 5.10 (d, 2H), 3.48 (s, 3H), 2.17-2.00 (m, 8H).

TH 2978

1H NMR (CDCl3, 400 MHz) δ 7.93 (d, 1H), 7.32-7.20 (m, 8H), 7.02 (d, 2H),6.96 (s, 1H), 5.30 (m, 1H), 3.40 (s, 3H), 2.17-2.00 (m, 8H), 1.56 (d,3H).

TH 2980

Starting with 2-(methylsulfonyl)phenol (78 mg). 1H NMR (CDCl3) δ: 1.64(d, 3H), 2.03-2.25 (m, 8H), 3.06 (s, 3H), 5.65 (m, 1H), 6.83 (d, 1H),7.10 (d, 1H), 7.13-7.35 (m, 3H), 7.50 (dd, 1H), 8.02 (d, 1H).

TH 2981

Starting with 2-(methylsulfonyl)phenol (113 mg). 1H NMR (CDCl3) δ:2.10-2.28 (m, 8H), 3.08 (s, 3H), 5.23 (d, 2H), 6.87 (d, 1H), 7.10 (d,1H), 7.13-7.35 (m, 3H), 7.50 (dd, 1H), 8.05 (d, 1H).

TH 2982

Starting with 3-[(Piperidin-1-yl)carbonyl]phenol (123 mg). ¹HNMR (CDCl₃)δ: 1.52 (br, 2H), 1.58 (d, 3H), 1.67 (br, 4H), 2.00-2.20 (m, 8H), 3.33(br, 2H), 3.68 (br, 2H), 5.59 (m, 1H), 7.03-7.07 (m, 2H), 7.10 (s, 1H),7.19 (d, 1H), 7.27 (d, 1H), 7.41 (t, 1H), 7.97 (d, 1H). ³¹PNMR (CDCl₃)δ: 31.2.

TH 2983

Starting with 3-[(Piperidin-1-yl)carbonyl]phenol (135 mg). ¹HNMR (CDCl3)δ: 1.51 (br, 2H), 1.66 (br, 4H), 2.10-2.20 (m, 8H), 3.32 (br, 2H), 3.68(br, 2H), 5.14 (d, 2H), 7.03 (s, 1H), 7.07-7.09 (m, 2H), 7.20 (d, 1H),7.25 (d, 1H), 7.42 (t, 1H), 7.98 (d, 1H). ³¹PNMR (CDCl3) δ: 32.0.

TH 2984

1H NMR (CDCl3) δ 7.99 (d, 1H), 7.42 (t, 1H), 7.32 (d, 1H), 7.3-7.24 (m,1H), 7.17 (s, 1H), 7.12-7.06 (m, 2H), 5.65-5.55 (m, 1H), 3.62 (t, 2H),3.42 (t, 2H), 2.22-1.85 (m, 12H), 1.58 (d, 3H).

TH 2985

1H NMR (CDCl3) δ 7.98 (d, 1H), 7.41 (t, 1H), 7.29-7.24 (m, 1H), 7.2-15(m, 1H), 7.09 (d, 1H), 7.1-7.0 (m, 2H), 5.65-5.55 (m, 1H), 3.6-3.45 (m,2H), 3.3-3.2 (m, 2H), 2.22-2 (m, 8H), 1.57 (d, 3H) 1.46-1.4 (m, 6H).

TH 2991

1H NMR (CDCl3) δ 7.99 (d, 1H), 7.57 (d, 2H), 7.5-7.42 (m, 4H), 7.38 (d,1H), 7.28 (s, 1H), 7.21 (dd, 1H), 7.11 (d, 1H), 7.38 (dt, 1H), 5.65-5.55(m, 1H), 2.16-1.92 (m, 8H), 1.57 (d, 3H).

TH 2992

1H NMR (CDCl3) δ 7.96 (d, 1H), 7.3-7.22 (m, 3H), 7.2-7.14 (m, 2H),7.07-7.0 (m, 3H), 7.08-6.9 (m, 3H), 5.65-5.55 (m, 1H), 2.22-2.0 (m, 8H),1.58 (d, 3H).

TH 2993

1H NMR (CDCl3) δ 8.0 (d, 1H), 7.47 (t, 1H), 7.32 (dd, 1H), 7.21 (d, 1H),7.2 (s, 1H), 7.14 (dd, 3H), 7.06 (d 1H), 5.65-5.55 (m, 1H), 4.3-3.9 (m,4H), 3.2-2.9 (m, 4H), 2.22-2.02 (m, 8H), 1.62 (d, 3H).

TH 3028

1H NMR (CDCl3, 400 MHz) δ 7.84 (d, 1H), 7.54-7.49 (m, 3H), 7.40-7.22 (m,6H), 7.11 (dd, 1H), 7.01 (dd, 1H), 6.71 (d, 1H), 5.42 (m, 1H), 2.12-1.90(m, 8H), 1.44 (d, 3H).

TH 3029

1H NMR (CDCl3, 400 MHz) δ 7.85 (d, 1H), 7.54-7.49 (m, 3H), 7.40-7.22 (m,6H), 7.11 (dd, 1H), 7.01 (dd, 1H), 6.75 (s, 1H), 5.00 (d, 2H), 2.14-2.03(m, 8H).

TH 3030

1H NMR (CDCl3, 400 MHz) δ 7.92 (d, 1H), 7.15 (t, 3H), 6.94 (t, 3H), 5.53(m, 1H), 2.34 (s, 3H), 2.18-1.96 (m, 8H), 1.53 (d, 3H).

TH 3031

1H NMR (CDCl3, 400 MHz) δ 7.92 (d, 1H), 7.17 (d, 2H), 7.13 (d, 1H),6.95-6.93 (bm, 3H), 5.08 (d, 2H), 2.34 (s, 3H), 2.18-2.05 (m, 8H).

TH 3032

1H NMR (CDCl3, 400 MHz) δ 7.98 (d, 1H), 7.35 (d, 2H), 7.30-7.22 (m, 5H),7.15 (s, 1H), 7.10 (d, 2H), 5.6 (m, 1H), 2.30 (s, 3H), 2.22-2.00 (m,8H), 1.60 (d, 3H).

TH 3033

1H NMR (CDCl3, 400 MHz) δ 7.98 (d, 1H), 7.33 (d, 2H), 7.26-7.20 (m, 5H),7.12 (s, 1H), 7.09 (d, 2H), 5.15 (d, 2H), 2.85 (s, 3H), 2.22-2.00 (m,8H).

TH 3034

1H NMR (CDCl3, 400 MHz) δ 7.94 (d, 1H), 7.41 (d, 2H), 7.16 (d, 1H), 6.99(t, 3H), 5.56 (m, 1H), 2.18-1.96 (m, 8H), 1.57 (d, 3H), 1.34 (s, 9H).

TH 3035

1H NMR (CDCl3, 400 MHz) δ 7.95 (d, 1H), 7.40 (d, 2H), 7.15 (d, 1H),7.00-6.99 (m, 3H), 5.11 (d, 2H), 2.18-2.08 (m, 8H), 1.33 (s, 9H).

TH 3036

1H NMR (CDCl3, 400 MHz) δ 8.01 (d, 1H), 7.62 (d, 2H), 7.31 (dd, 1H),7.16 (d, 1H), 7.07 (d, 2H), 5.62 (m, 1H), 2.20-2.00 (m, 8H), 1.59 (d,3H).

TH 3037

1H NMR (CDCl3, 400 MHz) δ 8.01 (d, 1H), 7.62 (d, 2H), 7.31 (dd, 1H),7.14 (s, 1H), 7.08 (d, 2H), 5.17 (d, 2H), 2.20-2.00 (m, 8H).

TH 3040

1H NMR (CDCl3, 400 MHz) δ: 7.99 (d, J=8.4 Hz, 1H), 7.62-7.57 (m, 4H),7.46 (t, J=7.6 Hz, 2H), 7.37 (t, J=7.2 Hz, 1H), 7.23 (dd, J=8.4, 1.6 Hz,1H), 7.13-7.11 (m, 3H), 5.61-5.58 (m, 1H), 2.22-1.81 (m, 8H), 1.58 (d,J=6.8 Hz, 3H) ppm.

TH 3041

1H NMR (CDCl3) δ 7.99 (d, 1H), 7.57 (d, 2H), 7.5 (d, 2H), 7.42 (d, 2H),7.25 (dd, 1H), 7.14-7.09 (m, 3H), 5.65-5.55 (m, 1H), 2.2-1.98 (m, 8H),1.59 (d, 3H).

TH 3042

1H NMR (CDCl3) δ 7.99 (d, 1H), 7.58-7.5 (m, 4H), 7.24 (dd, 1H),7.18-7.09 (m, 5H), 5.65-5.55 (m, 1H), 2.2-1.98 (m, 8H), 1.59 (d, 3H).

TH 3045

1H NMR (CDCl3, 400 MHz) δ: 7.99 (d, J=8.4 Hz, 1H), 7.62-7.57 (m, 4H),7.46 (t, J=7.6 Hz, 2H), 7.37 (t, J=7.2 Hz, 1H), 7.23 (dd, J=8.4, 1.6 Hz,1H), 7.13-7.11 (m, 3H), 5.61-5.58 (m, 1H), 2.22-1.81 (m, 8H), 1.58 (d,J=6.8 Hz, 3H) ppm.

TH 3050

1H NMR (CDCl3, 400 MHz) δ: 8.66 (d, J=6.4 Hz, 2H), 8.01 (d, J=8.4 Hz,1H), 7.67 (d, J=8.4 Hz, 2H), 7.49-7.47 (m, 2H), 7.28-7.27 (m, 1H),7.15-7.13 (m, 3H).

Example 2. In Vitro Human Tumor Cell Line Cytotoxicity Assays

In vitro proliferation data on the H460 non cell lung cancer human tumorcell line is reported above in the compound table. IC50 values arereported in micromolar and result from exposure of compound at variousconcentrations for 2 hrs followed by a wash step and addition of freshmedia followed by growth and cell viability staining and comparison to amedia only treated control.

Specifically, exponentially growing cells were seeded at a density of4×10³ cells per well in a 96 well plate and incubated at 37° C. in 5%CO₂, 95% air and 100% relative humidity for 24 hours prior to additionof test compounds. Compounds were solubilized in 100% DMSO at 200 timesthe desired final test concentration. At the time of drug addition,compounds were further diluted to 4 times the desired finalconcentration with complete medium. Aliquots of 50 μl of compound atspecified concentrations were added to microtiter wells alreadycontaining 150 μl of medium, resulting in the final drug concentrationreported. After drug addition, the plates were incubated for anadditional 2 hours at 37° C., 5% CO₂, 95% air, and 100% relativehumidity, then the drug was washed off and fresh medium was added andthe plates were incubated for addition 70 hrs at 37° C., 5% CO₂, 95% airand 100% relative humidity. At the end of this incubation, the viablecells were quantified using the AlamarBlue assay. The drug concentrationresulting in growth inhibition of 50% (IC₅₀) was calculated using Prismsoftware (Irvine, Calif.), and the results were listed in the table.

The H460 data above demonstrates a substantial anti-tumor effect withinhibition at down to low nanomolar levels for various compounds foronly a 2 hr. exposure.

TH 2870 was also tested in different cancer cell lines using thematerials and procedures as follows. 10*cell lysate buffer (cellsignaling technology, Cat. No. 9803); Protease Inhibitor Cocktail forMammalian Tissues (Sigma, Cat. No.P8340); Phosphatase InhibitorCocktails for Serine/Threonine Phosphatases and L-Isozymes of AlkalinePhosphatases (Sigma, Cat. No.P0044); Phosphatase Inhibitor Cocktails forTyrosine Protein Phosphatases, Acid and Alkaline Phosphatases (Sigma,Cat. No.P5726); BCA kit (Thermo, Cat. No. 23225); Primary antibody,mouse monoclonal AKR1C3 antibody (clone NP6.G6.A6; Sigma-Aldrich);Primary antibody, α-tubulin (clone B-5-1-2; Sigma-Aldrich); Secondaryantibody, Goat-anti-Mouse IgG HRp conjugated (A4416; Sigma-Aldrich) wereused. Cells were passaged two generations in good condition anddigested. The appropriate number of cells were inoculated in 6-cm cellculture dishes, and incubated at 37° C., 5% CO2 overnight. When thecells were grown to 80% density, the dish was removed from incubator.The medium was aspirated, washed twice with ice-cold PBS, and residualPBS was removed. An appropriate volume of ice-cold 1*cell lysate wasadded and incubated on ice for 10 minutes. Cell lysate was transferredto microfuge tubes chilled in ice, 4° C., 12,000 rpm and centrifuged for15 minutes. Supernatant was transferred into another microcentrifugetube. Cell lysates were diluted by a 10*cell lysates, and add ProteaseInhibitor Cocktail for Mammalian Tissues (Sigma, # P8340), PhosphataseInhibitor Cocktails for Serine/Threonine Phosphatases and L-Isozymes ofAlkaline Phosphatases, Phosphatase Inhibitor Cocktails for TyrosineProtein Phosphatases, Acid and Alkaline Phosphatases. The BCA proteinquantification kit for protein quantification was used with 1*celllysate to dilute the cell lysate to the same concentration.Corresponding samples were added on 5* SDS-loading buffer, heated to 85°C. for 10 minutes, and centrifuged briefly. The samples were saved at−20° C. or used directly for protein electrophoresis. The samples weresaved at −20° C. or used directly for protein electrophoresis. Thosesamples were electrophoresed according to standard practice, transferredto a membrane, the primary antibodies and then secondary antibody wereapplied according to the manufacturer's instructions. Odyssey infraredlaser imaging system was used to scan signals.

The results are shown below in FIGS. 1 and 2 and listed in the followingtables:

TABLE TH2870 sensitivity correlates with AKR1C3 expression in livercancer cells Cell line Expression RelIC50 (μM) Max Inhibition % C3A ++++0.0071 98.1 Hep G2 ++++ 0.0055 98.9 SNU-387 ++++ 0.0422 102.8 SNU-449++++ 0.0400 99.6 SNU-475 ++++ 0.0080 100.4 LIC-0903 ++++ 0.0819 96.3LIXC-003 ++++ 0.0054 44.6 LIXC-012 ++++ 0.0274 87.1 LIXC-086 ++++ 0.041092.8 LIXC-011 ++++ 0.0408 97.4 HCCC-9810 ++++ 0.0292 95.4 JHH-7 +++0.1074 69.8 PLC/PRF/5 +++ 0.4745 53.3 LIXC-002 +++ 0.0560 99.1 LIXC-004+++ 0.0313 83.6 LIXC-006 +++ 0.1156 71.7 HLE ++ 0.0842 80.5 LIXC-066 ++0.0941 75.4 HuCCT1 + 0.1252 66.7 SNU-423 + >1 43.3 Hep 3B2.1-7 / >1 8.1HLF / >1 22.5 SNU-182 / >1 19.4 SNU-398 / >1 15.3 SK-HEP-1 / >1 44.3

TABLE TH2870 sensitivity in prostate cancer cell lines 22RV1 Vcap DU145PC-3 LNCap MDA-Pca-2b NCI-H660 0.0019 0.0152 0.0429 0.1612 0.1616 >0.3>0.3

Example 3. In Vivo Human Tumor Xenograft Models and Antitumor Activity

Four human xenograft anti-tumor models utilizing non-small cell lungcancer H460, non-small cell lung cancer A549, melanoma A375 models, andrenal cell carcinoma 786-O were used to demonstrate the efficacy of thecompounds provided herein in 9 studies.

Specific pathogen-free homozygous female nude mice (nu/nu, Charles RiverLaboratories) were used. Mice were given food and water ad libitum andhoused in microisolator cages. Four to six week old animals wereidentified by microchips (Locus Technology, Manchester, Md., USA) at thetime of the experiments. All animal studies were approved by theInstitutional Animal Care and Use Committee at ThresholdPharmaceuticals, Inc.

All cell lines were from the American Type Culture Collection (ATCC,Rockville, Md., USA). Cells were cultured in the suggested medium with10% fetal bovine serum and maintained in a 5% CO₂ humidified environmentat 37° C.

Cells were mixed with Matrigel (50% with exception for 30% in the H460)and 0.2 ml per mouse were subcutaneously implanted to the flank area ofthe animals. When tumor size reached 100-150 250 mm3, mice wererandomized into experimental or vehicle groups with 10 mice/group andtreatment was started (Day 1). The tested compounds were formulated in5% DMSO in D5W. The regimens employed in the examples include IP,QD×5/wk (5 days on, 2 days off) as one cycle, for a total of 2 cycles;IP, once; IP, weekly for total 3 weeks; and IV, weekly for 3 weeks.Tumor growth and body weight were measured twice a week. Tumor volumewas calculated as (length×width2)/2. Drug efficacy was assessed as TumorGrowth Inhibition (TGI) and Tumor Growth Delay (TGD). TGI was defined as(1−ΔT/ΔC)×100, where ΔT/ΔC presented the ratio of the change in mean (ormedian, if variation within the group was relatively large) tumor volumeof the treated group and of the control group. TGD was calculated as theextra days for the treated tumor to reach 500 mm3 or 1000 mm3 ascompared to the control group. Animals were culled when individual tumorsize reached over 2000 mm3 or mean tumor volume exceeded 1000 mm3 in thegroup. Data are expressed as the mean±SEM. One-way analysis of variancewith Dunnett post comparison test (GraphPad Prism 4) or two-tailedstudent's t-test were used for analysis. A P level <0.05 was consideredstatistically significant.

Example 4. In Vivo Efficacy Results Example 4-A

Compounds provided herein were tested in vivo human tumor xenograftmodels and compared to standard chemotherapeutic agents such asgemcitabine, nab-paclitaxel. The experiments below demonstrate theantitumor effects of a compound provided herein on H460 non-small celllung cancer xenograft tumor. The compound was dosed as follows: daily IPdosing: 5 doses then 2 days off then 5 more doses starting at 100 mm³tumors on day 1 (10 animals per group median tumor volume). It iscontemplated that in some embodiments, the compounds provided herein areactivated by human and not by mouse enzymes. The antitumor effects andthe safety of administration are graphically illustrated in FIGS. 3-20below.

TGD TGD Max. BW Group TGI 500 1000 loss % Group 1: Vehicle 0.0% Group 2:GEM 60 mg/kg ip 42.7% 7 7 4.9% Q3D × 5 Group 7: TH2768 40 mg/kg ip104.1% 56 62 4.0% QD × 5/wk × 2 wks Group 13: TH2768 (40 mg/kg ip 104.8%55 59 5.4% QD × 5/wk × 2 wks) + CPT-11 (10 mg/kg ip QD × 5/wk × 2 wks)

Before this study, TH 2768 was tested in CD1 mice for toxicity under thesame dosing protocol as the efficacy study (daily IP 5 days on 2 daysoff and 5 days on). A maximum tolerated dose was determined where theaverage weight loss of the mice was less than 5% and no mouse lost morethan 20%. This dose was then used for the subsequent efficacy study. Inthe H460 study an antitumor effect of TH-2768 as a monotherapy issuperior to the effect of gemcitabine.

Example 4-B

Antitumor effects of compounds provided herein were determined on A 549non-small cell lung xenograft model in comparison with a chemotherapyagent, thiotepa. The dosing was as follows. Daily IP dosing: 5 dosesthen 2 days off then 5 more doses starting at 110 mm³ tumors on day 1(10 animals per group average tumor volume). The antitumor effects andthe safety of administration are graphically illustrated below.

Max. Group TGI TGD 500 BW loss % Group 1: Vehicle 0.0% Group 2:Thio-TEPA 2.5 mg/kg ip 68.3% 26 0.4% QD × 5/wk × 2 wks Group 3:Thio-TEPA 1.25 mg/kg ip 56.1% 17 0.0% QD × 5/wk × 2 wks Group 4: TH266010 mg/kg ip 60.7% 20 3.3% QD × 5/wk × 2 wks Group 6: TH2768 80 mg/kg ip104.4% >72 4.8% QD × 5/wk × 2 wks Group 7: TH2768 40 mg/kg ip 100.6% >720.0% QD × 5/wk × 2 wks Group 8: TH2850 20 mg/kg ip 88.1% >72 7.4% QD ×5/wk × 2 wks Group 9: TH2850 10 mg/kg ip 94.3% 70 0.9% QD × 5/wk × 2 wksGroup 10: TH2852 10 mg/kg ip 95.1% >72 0.0% QD × 5/wk × 2 wks Group 11:TH2870 20 mg/kg ip 102.3% >72 1.6% QD × 5/wk × 2 wks Group 12: TH2889 10mg/kg ip 90.1% 62 1.1% QD × 5/wk × 2 wks

Doses were selected by first doing a toxicity test in CD1 mice asdescribed above. The compounds were tested against Thio-tepa.

Example 4-C

his study employed an A375 melanoma human tumor xenograft model andvarious compounds provided herein were compared to thiotepa and theapproved anti melanoma drug, nab-Paclitaxel. The antitumor effects andthe safety of administration are graphically illustrated below.

Max. TGD TGD BW Group TGI 500 1000 loss % Group 1: Vehicle, qd × 5 × 2,ip 0 Group 2: Thio- 16.6% 3 2 0 TEPA, 2.5 mpk, qd × 5 × 2, ip Group47.4% 9 10 0 4: Abraxane, 30 mpk, 2 × /wk × 2, iv Group 5: TH2768, 40mpk, 36.7% 7 7 0 qd × 5 × 2, ip Group 6: TH2850, 10 mpk, 2.7% −2 0 2.8qd × 5 × 2, ip Group 7: TH2852, 10 mpk, 12.4% 3 1 2.6 qd × 5 × 2, ipGroup 8: TH2870, 20 mpk, 98.0% 24 >18 0 qd × 5 × 2, ip Group 9: TH2873,40 mpk, 65.0% 12 11 0 qd × 5 × 2, ip Group 10: TH2888, 10 mpk, 37.3% 6 64.8 qd × 5 × 2, ip Group 11: TH2889, 10 mpk, 75.6% 13 15 0 qd × 5 × 2,ip Group 12: TH2890, 10 mpk, 58.4% 10 10 6.3 qd × 5 × 2, ip

Example 4-D

The compounds were tested in another A549 model. The compounds weredosed as follows. Daily IP dosing: 5 doses then 2 days off then 5 moredoses starting at 100 mm³ tumors on day 1 (10 animals per group averagetumor volume). The antitumor effects and the safety of administrationare graphically illustrated below.

Max. TGD BW Lethal Group TGI 500 loss % Tox Group 1: Vehicle 0.9% 0Group 2: TH2870 20 mg/kg IP 95.0% >85 0.3% 0 QD × 5/wk × 2 wks Group 3:TH2883 10 mg/kg IP 93.5% >85 15.8% 5 QD × 5/wk × 2 wks Group 4: TH291110 mg/kg IP 88.7% 63 11.1% 0 QD × 5/wk × 2 wks Group 5: TH2931 5 mg/kgIP QD × 5 NA NA 25.0% 10 Group 6: TH2952 20 mg/kg IP 91.8% 70 1.2% 1 QD× 5/wk × 2 wks Group 7: TH2953 40 mg/kg IP 93.8% 64 1.6% 0 QD × 5/wk × 2wks Group 8: TH2955 40 mg/kg IP 78.9% 47 0.6% 1 QD × 5/wk × 2 wks Group9: TH2958 5 mg/kg IP 77.9% 44 2.1% 0 QD × 5/wk × 2 wks Group 10: TH287040 mg/kg 98.6% >85 2.0% 1 IV 2/wk × 2 wks

Example 4-E

The compound TH-2768 was tested in a renal cell carcinoma 786-O model.The compound was dosed as follows. Daily IP dosing: 5 doses then 2 daysoff then 5 more doses starting at 220 mm³ tumors on day 1 (10 animalsper group average tumor volume). The antitumor effects and the safety ofadministration are graphically illustrated below.

Group TGI Max. BW loss % Group 1: Vehicle 0.5% Group 2: TH2768, 40 mpk,ip, 73.0% 0.0% qd × 5/wk × 2 Group 5: Sunitinib, 40 mpk, po, 67.8% 0.3%qd × 5/wk × 2 Group 8: Sunitinib + TH2768 84.4% 2.3%

Example 4-F

The compounds TH-2953 and TH-3040 were tested in a H460 model. Thecompounds were dosed as follows. A dose-dependent TH-2953 was given IPonce, from 6.25 to 100 mg/kg, comparing with daily IP: 5 doses then 2days off then 5 more doses starting at 100 mm³ tumors on day 1 (10animals per group average tumor volume). TH-3040 was administered IPonce. The antitumor effects and the safety of administration aregraphically illustrated below.

Max. TGD TGD BW Group TGI 500 1000 loss % Group 1: Vehicle 0.0% Group 2:TH-2953, 100 mpk, ip, once 97.7% 24 27 0.0% Group 3: TH-2953, 50 mpk,ip, once 90.4% 19 19 0.0% Group 4: TH-2953, 25 mpk, ip, once 86.1% 18 200.2% Group 5: TH-2953, 12.5 mpk, ip, once 78.2% 18 21 0.0% Group 6:TH-2953, 6.25 mpk, ip, once 72.2% 16 17 0.0% Group 7: TH-2953, 40 mpk,ip, 105.8% 54 65 0.0% QD × 5/wk × 2ks Group 8: TH-3040, 100 mpk, ip,once 93.7% 20 23 0.0% Group 9: TH-3040, 25 mpk, ip, once 80.5% 17 171.3%

Example 4-G

The compounds TH-3040 and TH-3045 were tested in a H460 model. Thecompounds were dosed as follows. A dose-dependent TH-3040 or TH-3045 wasgiven IP weekly for 3 weeks, from 5 to 45 mg/kg starting at 100 mm³tumors on day 1 (10 animals per group average tumor volume). Theantitumor effects and the safety of administration are graphicallyillustrated below.

Max BW Group TGI TGD500 loss Group 1: Vehicle, ip, Q7D × 3 Group 2:TH-3040, 5 mpk, ip, Q7D × 3 103.5% 40 2.5% Group 3: TH-3040, 15 mpk, ip,Q7D × 3 104.3% 60 1.0% Group 4: TH-3040, 45 mpk, ip, Q7D × 3 106.4% 660.0% Group 5: TH-3045, 5 mpk, ip, Q7D × 3 104.0% 48 0.0% Group 6:TH-3045, 15 mpk, ip, Q7D × 3 104.8% 70 2.8% Group 7: TH-3045, 45 mpk,ip, Q7D × 3 106.3% 86 2.4%

Example 4-H

The compound TH-3040 was tested in a H460 model. The compound was dosedas follows: 5 or 1.5 mg/kg, IP, weekly for 3 weeks at 100 mm³ tumors onday 1 (10 animals per group average tumor volume), comparing withnab-Paclitaxel. The antitumor effects and the safety of administrationare graphically illustrated below.

TGD500, TGD1000, Max. Days (vs. Days (vs. BW Group TGI vehicle) vehicle)loss % Group 1: Vehicle 0.0% Group 6: TH3040 5 mg/kg, 101.9% 36 41 5.2%ip, Q7D × 3 Group 7: TH3040 1.5 mg/kg, 80.6% 15 19 7.2% ip, Q7D × 3Group11: ABX 30 mg/kg, iv, 49.7% 9 10 11.6% 2/wk × 2 wks Group 12: ABX10 mg/kg, iv, −12.5% −2 −1 1.2% 2/wk × 2 wks

Example 4-I

The compound TH-2870 was tested in a H460 model. The compound was dosedfollows. 1.5, 5 or 15 mg/kg, IV, weekly for 3 weeks at 250 mm³ tumors onday 1 (10 animals per group average tumor volume), comparing withdocetaxel. The antitumor effects and the safety of administration aregraphically illustrated below.

TGD500, TGD1000, Max. Days (vs. Days (vs. BW Group TGI vehicle) vehicle)loss % Group 1: Vehicle 0.0% Group 2: TH2870 1.5 mg/kg, 100.0% 18 187.6% iv, Q7D × 3 Group 3: TH2870 5 mg/kg, 121.3% 36 38 7.6% iv, Q7D × 3Group 4: TH2870 15 mg/kg, 121.6% 49 50 5.8% iv, Q7D × 3 Group 5:Doectaxel 10 mg/kg, 51.3% 6 9 12.4% iv, Q7D × 3

Taken together these studies demonstrate significant anti tumor efficacyin 4 different tumor cell lines relative to standard chemotherapeutics.

Example 5. Pharmacokinetics and Activation of TH 2870 by the AldoketoReductase, AKR1C3

Recombinant human AKR1C3 was diluted to 25 μg/mL in phosphate bufferedsaline (PBS), pH 7.4 (37° C.), containing 2 mM NADPH. TH2870 orprogesterone (positive control) in 30% methanol/70% water was added tothe reaction mixture at a final concentration of 5 μM and incubated at37° C. for 120 minutes. At various times up to 120 min, 50 μL of thereaction mixture was taken and 200 μL acetonitrile containingpropranolol as internal standard was added, vortex-mixed and centrifugedfor 10 min. The resulting supernatant (5 μL) was injected into aLC/MS/MS for quantitation of % remaining TH2870 and progesterone. Thecompounds were tested in duplicate.

Time % Remaining min TH2870 Progesterone 0  100%  100% 15 0.232%  70.8%30 0.0101%  49.2% 60 0.00% 20.1% 90 0.00% 10.6% 120 0.00% 6.40%

The data above demonstrates the rapid disappearance of TH2870 in thepresence of AKR1C3 while the known substrate, progesterone, is reducedslowly.

The pharmacokinetics of TH2870 in CD-1 mice following a singleintravenous bolus dose (5 mg/kg) and a single intraperitoneal dose (10mg/kg) were determined.

Route IV IP Dose (mg/kg) 5 10 Tmax (min) 2.00 5.00 Cmax (μg/mL) 6.794.02 Half-Life (min) 6.56 9.00 AUC (μg-min/mL) 57.8 43.5 Cl (L/min/kg)0.0865 — Vss (L/kg) 0.668 —

The pharmacokinetics of TH2870 were determined in Mouse/Nu-Foxn 1^(nu)NU/NU mice with A549 (non small cell lung), A375 (melanoma) and 786-O(renal cell) human tumor xenograft models following a singleintraperitoneal dose of 20 mg/kg. TH2870 concentrations in the brain,liver and tumor were only a fraction of the concentrations in plasma,ranging between 0.79% (brain) −32.6% (liver). In the A375 and 786-Oxenograft models, the concentrations of TH2660 was ˜24-29-fold and˜15-19-fold higher in tumor and liver than TH2870, suggestingpreferential activation of TH2870 in the tumor as compared to the liver.In the A549 xenograft, there was an even greater activation of TH2870 intumor as compared to the liver of ˜148-fold and ˜13-fold, respectively.

TH2870 TH2660 A549 A375 786-O A549 A375 786-O Tmax (min) 5.00 5.00 5.005.00 15.0 15.0 Cmax (μg/mL) 5.01 3.41 6.06 0.142 0.159 0.191 Half-Life(min) 11.3 14.7 12.3 28.4 30.2 10.6 AUC (μg-min/mL) 94.1 57.7 64.8 9.559.03 32.9

The pharmacokinetics of TH2873, TH2883, TH2888, TH2890, TH2901 andTH2926 were determined in CD-1 mice following a single intraperitonealdose.

TH2873 TH2883 TH2888 TH2889 TH2890 TH2901 TH2926 Tmax (min) 5.00 15.05.00 5.00 5.00 5.00 15.0 Cmax (μg/mL) 8.43 7.57 5.81 2.48 2.73 5.12 8.34Half-Life (min) 8.81 23.4 10.9 10.3 5.49 12.1 34.2 AUC (μg-min/mL) 126545 96.3 35.9 36.8 155 579

The pharmacokinetics of TH2660, the active metabolite, following asingle intraperitoneal dose of TH2873, TH2883, TH2888, TH2890, TH2901and TH2926 are shown below.

TH2873 TH2883 TH2888 TH2889 TH2890 TH2901 TH2926 Tmax (min) 5.00 30.030.0 30.0 15.0 30.0 30.0 Cmax (μg/mL) 9.85 0.147 0.3367 0.277 0.4550.265 0.038 Half-Life (min) 9.80 41.6 17.8 15.4 15.2 20.4 88.6 AUC(μg-min/mL) 125 11.7 20.6 15.8 17.8 15.3 5.06

The pharmacokinetics of TH2953 were determined in Mouse/Nu-Foxn 1^(nu)NU/NU mice with two non small cell lung human tumor xenograft models,

A549 H460 Dose (mg/kg) 10 40 10 Tmax (min) 30.0 30.0 15.0 Cmax (μg/mL)0.149 14.8 2.33 Half-Life (min) 100.00 91.3 142 AUC (μg-min/mL) 266 2341444

The pharmacokinetics of TH2660, the active metabolite, following asingle iintraperitoneal dose of TH2953 are shown below.

A549 H460 Dose (mg/kg) 10 40 10 Tmax (min) 15.0 60.0 NC Cmax (μg/mL)0.0202 0.0960 0.00 Half-Life (min) NC 9.69 NC AUC (μg-min/mL) 2.94* 39.80.00 *AUClast

A549 and H460, following a single intraperitoneal dose of 10 and 40mg/kg for A549 and 10 mg/kg for H460. TH2953 concentrations in thebrain, liver and tumor were 55.0-73.8%, 297-541% and 2.08-8.34% of theconcentrations in plasma in the A549 tumor xenograft. In the H460xenograft model, the concentrations of TH2660 were ˜9.6-fold and ˜2-foldhigher in tumor and liver than TH2953, suggesting preferentialactivation of TH2953 in the tumor as compared to the liver. In the A549xenograft, the preferential activation of TH2953 was more pronounced asthe concentrations of TH2660 in the tumor were ˜5-7-fold greater thanfor TH2953, while they were only ˜13-15% in the liver.

It should be understood that although the present invention has beenspecifically disclosed by certain aspects, embodiments, and optionalfeatures, modification, improvement and variation of such aspects,embodiments, and optional features can be resorted to by those skilledin the art, and that such modifications, improvements and variations areconsidered to be within the scope of this disclosure.

The inventions have been described broadly and generically herein. Eachof the narrower species and subgeneric groupings falling within thegeneric disclosure also form part of the invention. In addition, wherefeatures or aspects of the invention are described in terms of Markushgroups, those skilled in the art will recognize that the invention isalso thereby described in terms of any individual member or subgroup ofmembers of the Markush group.

1. A method of treating cancer comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of formulaI or a composition comprising the compound and at least apharmaceutically acceptable excipient or carrier thereby treating cancer

or a pharmaceutically acceptable salt, or a solvate of each thereof,wherein X¹⁰ is O, S, SO, or SO₂; A is C₆-C₁₀ aryl, 5-15 memberedheteroaryl, or —N═CR¹R²; each R¹ and R² independently is hydrogen, —CN,C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4-15 membered heterocycle,5-15 membered heteroaryl, ether, —CONR¹³R¹⁴, or —NR¹³COR¹⁴; each X and Zindependently is hydrogen or C₁-C₆ alkyl; Y is hydrogen, halo, or C₁-C₆alkyl; R is hydrogen or C₁-C₆ alkyl; each R¹³ and R¹⁴ independently ishydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₆-C₁₀ aryl, 4-15 memberedheterocycle, 5-15 membered heteroaryl, or ether; T isOP(Z¹)(NHCH₂CH₂Cl)₂, OP(Z¹)(NHCH₂CH₂Br)₂, OP(Z¹)(NH₂)(N(CH₂CH₂X¹)₂),OP(Z¹)(N(CH₂)₂)₂, or OP(Z¹)(N(CH₂CH₂Cl)₂)₂, wherein Z¹ is O or S, and X¹is Cl, Br, or OMs; and wherein the alkyl, cycloalkyl, aryl, heterocycle,heteroaryl, ether groups are optionally substituted.
 2. The method ofclaim 1, further comprising determining the AKR1C3 reductase level ofthe cancer in the patient using an AKR1C3 antibody prior to theadministration.
 3. The method of claim 2, further comprisingadministering to the patient the compound or the composition of claim 1if said AKR1C3 reductase level is equal to or greater than apredetermined value.
 4. The method of claim 1, further comprisingisolating a sample from the patient, determining an intratumoral AKR1C3reductase level of the cancer in the sample using an AKR1C3 antibody,and selecting the patient for therapy if the intratumoral AKR1C3reductase level of the cancer is equal to or greater than apredetermined level.
 5. The method of claim 1, wherein T isOP(O)(N(CH₂CH₂))₂, OP(O)(NHCH₂CH₂Cl)₂, OP(O)(NHCH₂CH₂Br)₂, orOP(O)(NH₂)(N(CH₂CH₂Cl)₂).
 6. The method of claim 1, wherein A isoptionally substituted C₆-C₁₀ aryl.
 7. The method of claim 1, wherein Ais optionally substituted phenyl.
 8. The method of claim 1, wherein A isoptionally substituted 5-15 membered heteroaryl.
 9. The method of claim9, wherein A is optionally substituted pyridyl.
 10. The method of claim1, wherein A is —N═CR¹R² where R¹ and R² are defined as in claim
 1. 11.The method of claim 1, wherein R is methyl.
 12. The method of claim 1,wherein the compound is


13. The method of claim 1, wherein the cancer is AKR1C3 reductaseoverexpressing cancer.
 14. The method of claim 13, wherein the cancer isliver cancer, non-small cell lung cancer or melanoma.
 15. The method ofclaim 1, wherein the patient is a human.